Hydro substituted prostanoic acids and esters

ABSTRACT

This disclosure describes certain 11-hydroxy and 11-deoxy-9-keto (or hydroxy)prostanoic acid derivatives useful as bronchodilators, anti-ulcer agents, or as intermediates.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of our copending application Ser. No. 540,052, filed Jan. 10, 1975, now abandoned, which is in turn a divisional of our application Ser. No. 355,349, filed Apr. 27, 1973, now U.S. Pat. No. 3,873,607, which is in turn a continuation-in-part of our application Ser. No. 274,768, filed July 24, 1972, and now abandoned.

BRIEF SUMMARY OF THE INVENTION

This invention relates to novel hydroxy substituted prostanoic acids and derivatives as well as to intermediates and methods for their preparation. These methods embrace novel and useful procedures for the preparation of prostaglandin E₁, 11-deoxyprostaglandin E₁, 13-dihydroprostaglandin E₁, and other known biologically important prostaglandin congeners. The novel compounds of this invention may be represented by the following general formula: ##STR1## wherein n is an integer having the value 1 or 2; R₁ is hydrogen, lower alkoxy, triphenylmethyl, or triphenylmethyl in which one or two of the phenyl rings is substituted with an alkyl or an alkoxy group having up to 3 carbon atoms; R₂ is a straight chain alkyl group having from 2 to 10 carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two alkyl groups each having from one to three carbon atoms, a straight chain alkenyl group having from 3 to 10 carbon atoms, a straight chain alkenyl group having from 3 to 10 carbon atoms and substituted with one or two alkyl groups having between them from 2 to 5 carbon atoms, or a straight chain alkynyl group having from 3 to 10 carbon atoms; R₃ is hydroxy or an alkoxy group having from 1 to 12 carbon atoms; Y is a divalent radical selected from the group consisting of those of the formulae: ##STR2## Z is a divalent radical selected from the group consisting of those of the formulae: ##STR3## wherein m is an integer from 3 to 8, inclusive, p is an integer from 2 to 6 inclusive, R₄ is an alkyl group having up to 3 carbon atoms, and R₅ is an alkyl group having up to 3 carbon atoms, a fluorine atom, or a phenyl group; R₆ is hydrogen or an alkyl group having up to three carbon atoms; R₇ is hydrogen or an alkyl group having up to 3 carbon atoms; and the moiety --C₁₃ --C₁₄ -- is ethylene, trans-vinylene, or cis-vinylene; with the first proviso that when n is 1, R₁ is hydrogen, R₇ is hydrogen, Z is --(CH₂)_(m) -- and --C₁₃ --C₁₄ -- is ethylene or trans-vinylene then R₂ does not include a straight chain alkyl group having from 2 to 10 carbon atoms; and with the second proviso that when Z is ##STR4## R₁ is hydrogen, R₂ is a straight chain alkyl group having from 2 to 10 carbon atoms and R₇ is hydrogen then --C₁₃ --C₁₄ -- is ethylene or cis-vinylene; and with the third proviso that when R₆ is alkyl then R₁ is hydrogen; and with the fourth proviso that only one unsaturated bond can be directly adjacent to C₁₅ ; and with the fifth proviso that when R₇ is an alkyl group then the groups attached to the C₈ position may have the 8α-alkyl(8-iso) configuration of the formula: ##STR5##

Embraced within the scope of the present invention are all the possible optical isomers of the above general formula. Also embraced within the scope of the present invention are the non-toxic, pharmaceutically acceptable salts of the novel compounds of the present invention when R₃ is hydroxy. The cations comprised in these salts include, for example, the non-toxic metal cations such as the sodium ion, potassium ion, calcium ion, and magnesium ion as well as the organic amine cations such as the tri(lower alkyl)amine cations (e.g., triethylamine, triethanolamine) procaine, and the like.

The novel compounds of the present invention are usually obtainable as oils having characteristic absorption spectra. They are relatively insoluble in water but are relatively soluble in common organic solvents such as ethanol, ethyl acetate, dimethylformamide, and the like. The cationic salts of the compounds when R₃ is hydroxy are, in general, white to yellow crystalline solids having characteristic melting points and absorption spectra. They are relatively soluble in water, methanol, and ethanol but are relatively insoluble in benzene, diethyl ether, and petroleum ether.

DETAILED DESCRIPTION OF THE INVENTION

The prostaglandins are a family of closely related compounds which have been obtained from various animal tissues, and which stimulate smooth muscle, lower arterial blood pressure, antagonize epinephrine-induced mobilization of free fatty acids, and have other pharmacological and autopharmacological effects in mammals. See Bergstrom et al., J. Biol. Chem. 238, 3555 (1963) and Horton, Experientia 21, 113 (1965) are references cited therein. All of the so called natural prostaglandins are derivatives of prostanoic acid: ##STR6## The hydrogen atoms attached to C-8 and C-12 are in trans-configuration. When the two side-chains (or the C-8 and C-12 hydrogens) are cis to each other, the compounds are referred to as 8-iso prostaglandins. The natural prostaglandins represent only one of the possible optical isomers. The compounds of this invention include all possible optical isomers.

The novel compounds of the present invention may be readily prepared from certain cycloalkenone intermediates which may be represented by the following general formula: ##STR7## wherein R'₃ is an alkoxy group having from 1 to 12 carbon atoms; and n and Z are as hereinabove defined.

The cycloalkenone intermediates may be readily prepared from 2-carbethoxycyclopentanone or 2-carbethoxycyclohexanone in accordance with the reaction schemes set forth in Flowsheets, A, B, C, I and J. ##STR8## wherein m and n are as hereinabove defined and X is iodo or bromo. In accordance with this reaction scheme, the cycloalk-2-en-1-ones (VIII) are developed by first converting 2-carbethoxycyclopentanone or 2-carbethoxycyclohexanone (I) to the sodium enolates thereof by means of sodium hydride in dimethoxyethane and then treating the sodium enolate with an ethyl ω-haloalkanoate (II). There is thus obtained the corresponding 2-carbethoxy-2-(ω-carbethoxyalkyl)cycloalkanone (III) which is then hydrolyzed and decarboxylated to afford the 2-(ω-carboxyalkyl)cycloalkanone (IV). This acid is then esterified with ethanol whereby the 2-(ω-carbethoxyalkyl)cycloalkanone (V) is obtained. The reaction conditions for carrying out the above sequence of reactions are well known in the art. The conversion of the cycloalkanone (V) to the enol acetate (VI) is effected by heating with acetic anhydride in the presence of p-toluenesulfonic acid. Preparation of the enol acetate (VI) usually requires heating for a period of from about 8 to 36 hours. During this period, it is preferable to allow by-product acetic acid to distill out in order to force the reaction to completion. The bromination of the enol acetates (VI) to the 2-bromocycloalkanones (VII) is preferably carried out in a two phase system as follows. A solution of bromine in chloroform is added to a rapidly stirred mixture of a solution of the enol acetate (VI) in chloroform and an aqueous solution of an acid acceptor such as calcium carbonate or soda ash. This addition is carried out at 0°-5° C. over a period of about half an hour, stirring is continued for an additional period of about half an hour to a few hours, and the product (VII) is then isolated by standard procedures. The dehydrobromination of the 2-bromocycloalkanones (VII) is preferably carried out in dimethylformamide with a mixture of lithium bromide and lithium carbonate at the reflux temperature for a period of about 30 minutes to an hour or so. The so formed cycloalk-2-en-1-ones (VIII) are also isolated by standard procedures well known in the art. Substitution of X--(CH₂)_(m) --C(R₄)₂ --CH₂ --CO₂ C₂ H₅ for (II) in Flowsheet A and carrying through the sequence of transformation illustrated therein is productive of the following cycloalk-2-en-1-one (VIIIa): ##STR9## wherein X, n, m and R₄ are as hereinabove defined.

The required cycloalk-2-en-1-one intermediates of general structure (XVI), wherein the side-chain has a lower alkyl group, fluorine atom or phenyl group alpha to the carbethoxy function, may be prepared in accordance with the following reaction scheme: ##STR10## wherein n, m and R₅ are as hereinabove defined and G is a lower alkyl or aryl group. In accordance with this reaction scheme, the 2-(ω-carbethoxyalkyl)cycloalk-2-en-1-ones (IX) are converted to the corresponding 1-methoximino-2-(ω-carbethoxyalkyl)-2-cycloalkenes (X) by treatment with methoxyamine. With the ring carbonyl function thus blocked it is possible to effect a preferential reduction of the ester group by treatment with diisobutylaluminum hydride. The resulting alcohol (XI) is converted to a tosylate derivative (XII), which undergoes displacement on treatment with the sodium salt of a diethyl R₅ -substituted malonate (XIII) to provide the disubstituted malonate derivatives (XIV). Hydrolysis and decarboxylation as well as concomittant cleavage of the methoximino blocking group provides the desired 2-(ω-carboxy-ω-R₅ -substituted-alkyl)cycloalk-2-en-1-ones (XV), which are readily converted to the corresponding ester (XVI) by the usual procedure via the acid chloride and subsequent treatment with the appropriate alcohol in the presence of a tertiary amine.

The requisite 2-(ω-carbethoxy-ω-1-oxa-alkyl)cyclo-alk-2-en-1-ones (XXII) and 2-(ω-carbethoxy-ω-1-thia-alkyl)-cycloalk-2-en-1-ones (XXVI) may be prepared in accordance with the reaction schemes of Flowsheet C, wherein n and m are as hereinbefore defined. ##STR11##

In accordance with the reaction scheme shown in Flowsheet C, for the preparation of the oxa derivative (XXII), an appropriate 2-(ω -carbethoxyalkyl)cycloalk-2-en-1-one (XVII) is converted to the corresponding methoxime (XVIII), the ester function of which is then preferentially reduced with diisobutylaluminum hydride to afford the methoxime alcohol (XIX). The alcohol (XIX) is converted on treatment with n-butyl lithium to the lithio alcoholate, which then is O-alkylated by reaction with ethyl bromoacetate to provide (XX). Hydrolysis with acetone-aqueous hydrochloric acid furnishes the deblocked keto-acid (XXI), which is then reesterified with ethanol in the presence of p-toluenesulfonic acid to give the required 2-(ω-carbethoxy-ω-1-oxa-alkyl)cyclo-alk-2-en-1-one (XXII). O-Alkylation can also be accomplished by treatment of the lithio alcoholate of (XIX) with sodium or other metal salt of bromoacetic acid, in which case the free carboxylic acid corresponding to ester (XX) is obtained. Hydrolysis as for (XX) provides the keto acid (XXI).

The preparation of the thia derivative (XXVI), proceeds from the intermediate alcohol (XIX), which after conversion to the tosylate intermediate (XXIII) and reaction with the sodium salt of ethyl mercaptoacetate furnishes intermediate (XXIV). Deblocking of XXIV with a acetone-aqueous hydrochloric acid provides the keto-acid (XXV), which on re-esterification with ethanol gives the required 2-(ωcarbethoxy-ω-1-thia-alkyl)cycloalk-2-en-1-ones (XXVI).

Certain of the 11-deoxy-9-keto(or hydroxy)-prostanoic acid derivatives of this invention, as defined in the general formula on page 1 above, may be prepared from cycloalkenone (XXXI) and the triphenylmethoxy substituted 1-alkyne (XXVII) as depicted in Flowsheet D. In Flowsheet D, n R₃, R'₃ and Z are as hereinabove defined; R'₂ is a straight chain alkyl group having from 2 to 10 carbon atoms, a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two alkyl groups each having from one to three carbon atoms, a straight chain alkenyl methyl group having from two to nine carbon atoms, or a straight chain alkenyl methyl group having from two to nine carbon atoms and substituted with one or two alkyl groups having between them 2 to 5 carbon atoms; and R is a lower alkyl group. ##STR12##

In accordance with the reaction scheme of Flowsheet D, the triphenylmethoxy substituted 1-alkyne (XXVII) is treated with diisobutylaluminum hydride (XXVIII). This reaction of the 1-alkyne (XXVII) with diisobutylaluminum hydride (XXVIII) provides the alane (XXIX) containing the trans-double bond and is carried out in an inert solvent such as benzene, toluene, and the like at temperatures in the range of 40°-60° C. for several hours. It can also be carried out in a solvent such as tetrahydrofuran, usually in an approximate 2:1 mixture with benzene or hexame; in which case the reaction requires somewhat more vigorous conditions, usually treating at about 70°-75° C. for about eighteen hours. The subsequent reaction with methyl or n-butyl lithium (R-Li) is preferably carried out in a mixture of the above solvents with an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran and the like. This reaction is rapid and is preferably carried out at 0°-10° C. with cooling. The conjugate 1,4-addition of the resulting alanate salt (XXX) to the cycloalk-2-en-1-one (XXXI) is preferably carried out at ambient temperatures for a period of 12 to 24 hours. This reaction is also best carried out in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like. The intermediate alanate-enolate adduct is then carefully hydrolyzed in situ with dilute hydrochloric acid with cooling, and the products (XXXII) are isolated in the usual manner well know in the art. Removal of the triphenylmethyl blocking group can then be accomplished by treating with weak acid. A preferred procedure involves heating at 45° C. for 3.5 hours in a solvent system consisting of acetic acid:tetrahydrofuran:water in the proportion of 4:2:1. Saponification in the usual manner of the resulting alkyl ester (XXXIII, R₃ ═alkoxy) provides the corresponding carboxylic acid (XXXIII, R₃ ═OH).

All available evidence leads us to the conclusion that in the product (XXXIII) the two sided-chains attached to C₈ and C₁₂ are trans to each other. However, we are not certain of the configurational relationship in product (XXXII) as it is obtained directly from the alanate process. These products may have the side-chains in a trans or cis-relationship or they may be a mixture containing both the trans- and cis-isomers. This is indicated in the nomenclature of the compounds involved by the designation of 8ξ. In order to ensure a trans-relationship in both (XXXII) and (XXXIII) these products can be submitted to conditions known in the literature to equilibrate the cis-8-iso-PGE₁ to a mixture containing about 90% of the trans-product. These conditions involve treatment with potassium acetate in aqueous methanol for 96 hours at room temperature.

The triphenylmethyl blocking group for the hydroxy function in (XXVII) etc. is an important feature of this process and other oxygen blocking groups, e.g., tetrahydropyranyl and alkyl, are not compatible with a clean cis-addition of diisobutyl aluminum hydride (XXVIII) to the alkyne (XXVII) to provide the desired trans-vinyl function. Alternative pressures for the preparation of novel lithio alanate reagents useful for the introduction of the Δ¹³ -trans 15-oxy β-chain by conjugate 1,4-addition are illustrated in Flowsheet K further below.

The intermediates for the introduction of the Δ¹³ -15-hydroxy side-chain are an integral part of this invention and they may be represented by the following general formulae (A), (B), (C), (D) and (E) wherein R'₂ is as hereinabove defined, R is a lower alkyl group, not necessarily the same for each use, and R' is an alkyl group having from one to ten carbon atoms are necessarily the same for each use, W₁ is lower alkoxy, triphenylmethyl, or a triphenylmethyl group in which one or two of the phenyl rings is substituted with a lower alkoxy group; W₂ is lower alkoxy, triphenylmethyl, a triphenylmethyl group in which one or two of the phenyl rings is substituted with a lower alkoxy group, tetrahydropyranyl, α-(lower alkoxy) substituted lower alkyl, t-butyl, or a tri-(lower alkyl)silyl group; X₁ is iodo or bromo; s is an integer having the value of one to three inclusive, and t is an interger having the value of one to three inclusive, with the proviso that the sum of s and t must be equal to four. ##STR13##

The alanate conjugate addition procedure is also useful for the synthesis of prostaglandin E₁ (XL) as illustrated in Flowsheet E. This reaction sequence is carried out in the same manner as described for the sequence in Flowsheet D. It is to be noted that the introduction of the Δ¹³ -15-oxy chain proceeds trans to the 11-oxy function. For this synthesis, it is best to use the tetrahydropyranyl or trialkylsilyl esters, since these esters can be hydrolyzed under conditions compatible with the stability of the β-ketol feature of prostaglandin E₁. Alkyl esters would be hydrolyzed by fermentation with Baker's Yeast. The tetrahydropyranyl or trialkylsilyl, and triphenylmethoxy blocking groups are removed by mild acid treatment, for example with acetic acid:tetrahydrofuran:water (4:2:1) as described hereinabove. Application of the lithio alanoate conjugate addition process to the synthesis of prostaglandins E₂ and E₃ is described below in connection with Flowsheet N. ##STR14##

The 13-dihydro derivatives (D₁₃ -C₁₄ is ethylene) of this invention can be prepared by reduction of the Δ¹³ function in the corresponding 13-prostenoic acids or esters. This reduction can be accomplished by hydrogenation. However this procedure is not cleanly applicable in the presence of other double bonds in the molecule. In the latter instance the 13-dihydro derivatives are preparable via conjugate addition of a Grignard derivative (XLII) to cycloalkenone (XLI) in the presence of a catalyst such as the tributylphosphine-cuprous iodide complex as set forth in Flowsheet F, wherein n, Z, R₂ and R'₃ are as hereinabove defined; Q is a blocking group; and x is chlorine, bromine or iodine, preferably bromine or iodine. The blocking group (Q) for the hydroxyl function in (XLII) can be any group table to the Grignard reagent and which can later be removed by chemical treatment (e.g., mild hydrolysis or catalytic hydrogenolysis in the absence of carbon to carbon double bonds elsewhere in the molecule) to which the remainder of the molecule is stable. Suitable blocking groups, therefore, may be, for example, benzyl, diphenylmethyl, triphenylmethyl, tetrahydropyranyl, or a moiety of the formula: ##STR15## wherein R₁₁ is hydrogen, methyl or ethyl. Among the above-described blocking groups, we have found tert-butyl to be particularly convenient and useful. ##STR16##

In accordance with the above reaction scheme, the conjugate 1,4-addition of a 3-(substituted hydroxy)alkyl or alkenyl magnesium halide (XLII) to a cycloalk-2-en-1-one (XLI) is carried out in the presence of a catalyst. In general, Grignard reactions with conjugated ketones provide 1,2-addition products; conjugate 1,4-addition is usually accomplished when the reaction is carried out in the presence of a cuprous chloride or cuprous acetate catalyst. It is therefore most unexpected that the reaction of the cycloalkenone (XLI) with a Grignard reagent (XLII) in the presence of either of the aforementioned catalysts does not give appreciable movements of the desired 1,4-conjugate addition products. The novel feature of our process is provided by the use, as a catalyst, of a cuprous halide complex with a trisubstituted phosphine, a trialkyl phosphonate, a tertiary amine or a heterocycle containing a basic nitrogen (e.g., pyridine). We have found it preferable to use tributylphosphine-cuprous iodide complex; (C₄ H₉)₃ P.CuI. The reaction is best carried out in the usual way in an ether-type solvent such as diethyl ether, dibutyl ether, tetrahydrofuran, and the like, at room temperature for a period of time of from two to eighteen hours. The intermediate magnesium halide-enolate adduct is then hydrolyzed in situ, preferably with ammonium chloride, at room temperature and the product (XLIII) is isolated in the usual manner well known in the art.

When the blocking group is a tertiary alkyl moiety such as tert-butyl, deblocking of (XLIII) to affore (XLIV) is conveniently effected by treatment with glacial trifluoroacetic acid at from -5° C. to 10° C. for a period of one to three hours. Since this procedure may lead to partial trifluoroacetylation of the free hydroxy function, it is preferably followed by treatment with aqueous ammonia (about 1. On concentration) for about 15 minutes at ambient temperatures. When the blocking group is tetrahydropyranyl, its removal is readily effected with dilute acid. When the blocking group is a moiety such as benzyl, diphenylmethyl or triphenylmethyl, deblocking of (XLIII) is conveniently effected by catalytic hydrogenolysis, procedures for which are well known in the art. In the instance of triphenylmethyl, deblocking is preferably effected by treating with acetic acid:tetrahydrofuran: water (4:2:1) at about 45° C for about 3.5 hours.

Mild acid treatment results in hydrolysis of the tetrahydropyranyl esters; alkyl esters can be hydrolyzed by the usual saponification techniques.

When the cycloalkanone esters (XLIII) are formed by quenching of the reaction mixture with aqueous ammonium chloride solution, the relative stereochemical relationship of the two side-chains is not known with certainty. Therefore, the bond liniing the Grignard-derived side-chain to the cycloalkyl ring is indicated by a bond in (XLIII). However, in any case, the subsequent deblocking and ester hydrolysis procedures ensure the development, at least in predominant proportion, of the thermodynamically favored trans-relationship between the two side-chains, as is depicted in structure (XLIV) of the reaction scheme.

An alternative method for the introduction of the Δ¹³ -15-hydroxy side-chain involves 1,4-conjugate addition to cycloalkenone (LV) of a vinyl Grignard reagent [(LIII) + (LIV)]in the presence of a catalyst such as the tributylphosphine cuprous iodide complex followed by deblocking. From this process, in addition to the product (LVIII) containing the C₁₃ -C₁₄ moiety as a trans-vinylene function there also is obtained the corresponding product (LIX) in which the C₁₃ -C₁₄ moiety is a cis-vinylene function. These novel cis-Δ¹³ derivatives are also embraced within the scope of this invention. The reaction sequence for the "vinyl" Grignard process is illustrated in flowsheet G, which follows, and in which W₂, n, Z, R₃ and R'₃ are as hereinabove defined, and R"₂ is a straight chain alkyl group having from 2 to 10 carbon atoms, or a straight chain alkyl group having from 2 to 10 carbon atoms and substituted with one or two alkyl groups having from one to three carbon atoms. ##STR17##

In accord with the reaction sequence of Flowsheet G the vinyl Grignard reagent (LIII + LIV), is prepared under an inert atmosphere in a relatively limited amount of anhydrous tetrahydrofuran. More vigorous conditions (e.g., heating in an oil bath at 70°-80° C., one hour), for the formation of the Grignard reagent (LIII + LIV) favors the proportion of Δ¹³ -cis isomer (LIX) in the product of conjugate addition. Milder conditions (for example 35°-47° C., one hour) favors the proportion of Δ¹³ -trans isomer (LVIII) in the final product.

Conjugate addition of the vinyl Grignard reagent mixture [(LIII) + (LIV) to cycloalkenone (LV) is then preferably carried out by addition of the Grignard to the cycloalkenone dissolved in an ether type solvent, e.g., diethylether, containing a catalyst such as the tributylphosphine-cuprous iodide complex at a temperature of about 0° C. After a period of about thirty minutes to three hours the reaction mixture is poured onto aqueous concentrated ammonium chloride solution to give (LVI) + (LVII). As explained hereinabove, at this stage the relationship of the two side-chains to each other is not determined. In any event, deblocking the 15-hydroxy function with weak acid (which procedure also hydrolyzes trialkylsilyl or tetrahydropyranyl esters) provides the product (LVIII) and (LIX) in which the chains are trans to each other. In the instance of alkyl esters, saponification provides the corresponding carboxylic acids. The Δ⁻⁻ -cis and Δ¹³ -trans-isomers can be separated from each other by the usual techniques of chromatography; particularly useful is liquid-liquid partition chromatography.

The precursor 3-hydroxy-1-trans-alkenyl bromides (LI) can be prepared, as illustrated in Flowsheet G, by condensation of acetylene (XLV) with an acid chloride (XLVI) in the presence of aluminum trichloride. The resulting 3-oxo-1-chloro-trans-1-alkylene (XLVII) is then converted to the corresponding 1-bromo derivative (XLVIII), by reaction with excess lithium bromide. This reaction is preferably carried out in ketone solvents, such as 2-pentanone or acetone. Reduction of the 3-keto function in (XLVIII), with for example, sodium borohydride provides the alcohol (LI). The alcohol function is then blocked to give (LII). Alternatively, the 3-oxo vinyl bromide (XLVIII) can be prepared directly from the acyl bromide (L) and acetylene (XLIX) in the presence of aluminum tribromide, preferably in ethylene dibromide.

The "vinyl Grignard" procedure outlined in Flowsheet G represents a novel, useful and convenient procedure for the synthesis of 13-prostenoic acids and the novel Grignard reagents represented by formulae (LIII) and (LIV) are to be considered as embraced within the scope of this invention.

The "vinyl Grignard" technique can also be applied to a useful synthesis of prostaglandin E₁ and the novel Δ¹³ -cis-prostaglandin-E₁ as illustrated in Flowsheet H, below. Thus, treatment of cyclopentenone (LX) with Grignard [(LXI + (LXII)] in accordance with the considerations discussed hereinabove, provides the conjugate addition products (LXIII) plus (LXIV), mild acid hydrolysis of which furnishes prostaglandin E₁ (LXV) and Δ¹³ -cis prostaglandin E₁ (LXVI), separable by chromatography. ##STR18##

The preparation of the cycloalkenone intermediates (LXXVI, LXXVII) bearing a cis double bond in the carboxylic acid side chain can be accomplished by the sequence illustrated in Flowsheet I, which follows and in which n and p are as hereinabove defined. . ##STR19##

In the above Flowsheet I, the sequence wherein a 2-carbalkoxycycloalkanone (LXVII) is transformed to a 2-(β-hydroxyethyl)cycloalk-2-en-1-one (LXXIII) is carried out in the manner described in Flowsheet A. Methyl ether cleavage of the corresponding 2-(β-methoxymethyl)cycloalkenone is achieved by treating with boron tribromide. Oxidation of the alcohol (LXXIII) with Collins reagent [chromium trioxide-pyridine complex in methylene chloride under anhydrous conditions; J. C. Collins, W. W. Hess, and F. J. Frank, Tetrahedron Letters, 3363 (1968)] provides the aldehyde (LXXIV), which is then treated in anhydrous dimethylsulfoxide with the ylid (LXXV) prepared from an (ω-carboxyalkyl)triphenyl phosphonium bromide and sodium hydride. The use of dimethylsulfoxide as a solvent for this reaction leads to the predominant formation of the desired cis double bond derivative (LXXVI). The acid function in (LXXVI) can be esterified in the usual fashion; with diazomethane, the methyl ester (LXXVII) is obtained.

Cyclopentenones such as (LXXVI wherein n=1) may also be prepared by the sequence illustrated in Flowsheet J, which follows and in which p is as hereinabove defined. ##STR20##

In Flowsheet J above the bicyclic hemiacetal (LXXVIII) [P. A. Grieco, Journ. Org. Chem., 37, 2363 (1972)] is treated with ylid (LXXIX) to give the 1-hydroxy-3-cyclopentene (LXXX). Oxidation with Jones reagent gives the corresponding ketone (LXXXI), which on base treatment furnishes the required cyclopentenone (LXXXII), which can then be esterified in the usual manner.

Certain of the intermediates illustrated in Flowsheets I and J, in particular the compounds of formulae (LXXI), (LXXII), (LXXIII), (LXXIV), (LXXVI) (LXXVII) (and related esters), (LXXX) and (LXXXI) are novel and useful compounds and are embraced within the scope of this invention.

Alternative procedures for the preparation of the alanate intermediates to that discussed in connection with Flowsheet D above are illustrated below in Flowsheet K, wherein R', R'₂, R"₂ and W₂ are as hereinabove defined. ##STR21##

In accordance with the sequence of Flowsheet K above the 1-iodo-trans-1-alkenyl-3-oxo derivative (LXXXIV) is prepared by iodide interchange, preferably in acetone or similar ketone, from the corresponding chloride (LXXXIII), the preparation of which is described in connection with Flowsheet G above. Reduction of (LXXXIV) to the alcohol (LXXXVI) can be accomplished in the usual manner wth sodium borohydride. The hydroxy function is then blocked to give (LXXXV, R'₂ --R"₂). Treatment of the acetylene, ##STR22## with one equivalent of disiamylborane (prepared in situ from diborane and 2-methyl-2-butene) and then with excess anhydrous trimethylamine oxide followed by treatment with an aqueous solution of excess sodium hydroxide and a tetrahydrofuran solution of excess idodine is also productive of (LXXXV). Treatment of the trans-1-alkenyl iodide (LXXXV) at low temperatures, preferably at about -30° C. to -78° C., in an inert solvent, e.g., hexane or toluene, with an alkyl lithium, e.g., butyl lithium, provides the trans-1-alkenyl lithium reagent (LXXXVII). Treatment of this lithio derivative with a tri-alkyl aluminum furnishes the trasns-1-alkenyl trialkyl alanate (LXXXVIII). Treatment of a dialkyl aluminum chloride with two molar equivalents of lithio reagent (LXXXVII) gives the bis(trans-1-alkenyl)dialkyl alanate (LXXXIX) and treatment of an alkylaluminum dichloride with three molar equivalents of lithio reagent (LXXXVII) affords the tris(trans-1-alkenyl)alkyl alanate (XC).

Each of the three types of alanates, (LXXXVIII), (LXXXIX) and (XC), can be utilized for 1,4-conjugate addition reactions as described hereinabove in connection with Flow-sheets D and E above. Thus, substitution of (LXXXVIII), (LXXXIX) or (XC) for alanate (XXX) in Flowsheet D will provide the indicated products of the Flowsheet. Similarly, substitution of (LXXXVIII), (LXXXIX) or (XC) in which R'₂ is n-pentyl for alanate (XXVII) in Flowsheet E provides prostaglandins E₁. In general the mono alkenyl alanate (LXXXVIII) is preferred because it is more economical in the use of vinyl halide.

With regard to the cycloakenones of Flowsheets D, E, F, G and H it should be noted that the blocking groups for the 4-hydroxy function as well as for the carboxylic acid may also be a tri-alkylsilyl group, e.g., trimethylsilyl, dimethyl-t-butylsilyl or dimethylisopropylsilyl. Cyclopentenones blocked in this manner are illustrated below in formula (XCI) and (XCII)wherein m, n, Z and R' (not necessarily the same for each use) are as hereinabove defined. ##STR23##

All the novel products of this invention exclusive of certain intermediates bear a hydroxy or oxy function substituted at or at what ultimately becomes the C₁₅ atom of the product prostanoic acids and esters. Thus in at least most instances a 15-"normal" and a 15-"epi" racemate is obtained in at least near equal proportions. Each of the racemates contains equal amounts of the enantiomer wherein C₁₅ is in the S configuration and the enantiomer wherein it is in the R configuration. The racemates are separable from each other by the usual techniques of chromatography. Also, resolution in the usual way of the β-chain precursor [for example, the resolution of 3-hydroxy-1-octyne is described in the literature [see R. Pappo, P. Collins and C. Jung. Ann. N. Y. Acad. of Science, 180 (Prostaglandins), 64(1971); J. Fried et al., ibid, p. 381.] Resolution prior to the conjugate addition operation will provide the diastereomers wherein the C₁₅ atom is either in the 15(S) or 15(R) configuration, as desired. Separation of the diastereomers so obtained, for example, by chromatography, will give the fully resolved (d and 1) products provided there are no asymmetric carbon atoms other than at C₈ and C₁₂. The presence of other asymmetric sites requires additional resolution steps in order to obtain a single atipode. The compounds of this invention embrace all possible optical isomers.

The 11-deoxy-9-keto derivatives (XCIV) of this invention can be converted to the corresponding 9-hydroxy derivatives. If this conversion is effected with sodium borohydride, the product is a mixture of 9α- and 9β-hydroxy derivatives (XCIII) and (XCV) as set forth in the following reaction scheme: ##STR24## wherein R₂, R₃, R₆, R₇, Z, n and --C₁₃ -C₁₄ -- are as hereinabove defined. In general, when the reaction is carried out with lithium perhydro-9b-boraphenalyl hydride [H. C. Brown and W. C. Dickason, Journ. Amer. Chem. Soc., 92, 709 (1970)] the product is at least predominately the 9α-hydroxy derivative (XCIII), wherein the 9-hydroxy group is cis to the side-chain attached to C₈.

In accordance with accepted convention, an α-substituent at the 8-, 9-, or 12-positions is behind the plane of the paper whereas a β-substituent at these positions is in front of the plane of the paper. This is usually represented by a bond for an α-substitutent, a bond for a β-substitutent, and a bond where both are indicated. Thus, the 9-hydroxy derivatives may be variously represented as follows: ##STR25##

A useful procedure for the introduction of the 15-lower alkyl group (R₆) is illustrated by the sequences of Flowsheet M, which follows. ##STR26##

In Flowsheet M above n, Z, R₂, R₇ and R₆ are as hereinabove defined. In the sequence depicted in Flowsheet M the 9,15-diol (XCVI) is treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (XCVII), which preferentially oxidizes the allylic alcohol function at C₁₅ to give the 15-ketone (XCVIII). Blocking of the remaining hydroxy function as a trimethylsilyl ether give (IC) which is reacted with the alkyl Grignard, R₆ MgI, to give the 15-alkyl-15-hydroxy derivative (CI). Hydrolysis of the silyl ether blocking group then give the diol ester (C), saponification of which gives (CII). Oxidation of the secondary 9-hydroxy function in (C) provides the 15-alkyl-9-oxo ester (CIII), saponification of which furnishes (CIV). (A similar sequence can be effected with the Δ¹³ -cis-series.)

The processes of this invention are aslo useful for the preparation of prostaglandin E₂ and prostaglandin E₃ and thus also PGF₂α and PGF₃α by reduction, for example with lithium perhydro-9b-boraphenalyl hydride. The 4-hydroxycyclopentenone intermediate (CXI) required for these syntheses is prepared in accordance with the procedure illustrated in Flowsheet N which follows and in which is also shown the transformation of this compound to prostaglandins E₂ and E₃. In Flowsheet N, J is an appropriate blocking group for the hydroxy and ester function in (CXI) which is compatible with the conjugate addition reaction and also is ultimately removable by acid-catalyzed hydrolysis or other techniques which will not disrupt the sensitive 11-oxy-9-keto system in the products (CXIII), (CXV), (CXVIII) and (CXVII). Particularly useful for this purpose are the tetrahydropyranyl group and various trialkylsilyl groups (e.g., dimethylispropylsilyl, trimethylsilyl, dimethyl-t-butylsilyl and the like. ##STR27##

In accordance with the above reaction scheme the 3,4-epoxylactol (CV) [E. J. Corey and R. Noyori, Tetrahedron Letters, 311 (1970)] is treated with the ylide (CVI) to give the 3,4-epoxycyclopentanol (CVII) bearing the α-chain of the prostaglandin 2 series. Oxidation (for example with H₂ CrO₄.H₂ SO₄ -ether or Jones reagent) of (CVII) provides the epoxy ketone (CVIII), mild base treatment of which results in the initial formation of the 4-hydroxycyclopent-2-en-1-one (CXI) and the isomeric 3-hydroxycyclopent-4-en-1-one (CX) as a mixture. Further treatment of this mixture with dilute base under mild conditions (preferably pH 10.3-10.6 for 24 hours) results in the isomerization of the 3-hydroxy isomer (CX) to the desired (CXI). We believe that the transformation of the epoxy ketone (CVIII) to the hydroxycyclopentenones (CX) and (CXI) and the isomerization of (CX) to (CXI) may take place through the intermediacy of the 3,4-diol (CIX). It is also conceivable that isomerization of (CX) to (CXI) procedes via the epoxy derivative (CVIII) or the corresponding α-epoxide (CXIb); it is further conceivable that (CVIII) procedes to (CX) and (CXI) directly without the intermediacy of (CIX). Another possible intermediate for the isomerization of (CX) to (CXI) is the corresponding diene (CXIa). The preparation of (CXI) is also possible via the α-epoxide series from (CXIc) via the α-epoxide corresponding to (CVII) and (CVIII) such as (CXIb) or via a mixture of the α and β epoxides. In practice, it is most conventient to utilize a mixture of α- and β-epoxides (CXIc and CV). The hydroxy and acid function in the 4-hydroxycyclopentenones (CXI) are then appropriately blocked to give (CXII). Appropriate blocking groups are tetrahydropyranyl, trimethylsilyl, dimethyl-isopropylsilyl, dimethyl-t-butylsilyl and the like. Treatment of (CXII) with the lithio alanate (CXIV) or its equivalent (see the discussion hereinabove for Flowsheets K and E) gives the conjugate addition product (CXIII) in which the configuration at C₈ is undetermined. Mild acid treatment, for example with acetic acid:tetrahydrofuran:water,(4:2:1), of (CXIII) results in the removal of blocking groups, and if necessary equilibration to the all-trans configuration, to give prostaglandin E₂ (CXV). Similarly treatment of (CXII) with the lithio alanate (CXVI) gives prostaglandin E₃ (CXVII).

Substitution in Flowsheet N, of ylide (CXIX), wherein p is as hereinabove defined, for the ylide (CVI) provides, by transformations analogous to those described in Flowsheet N [(CV) to (CXI) and (CXII)], the 4-hydroxycyclopent-2-en-1-ones (CXX) and their blocked ether-esters (CXXI). These novel and useful intermediates are a part of the present invention. ##STR28##

The 8β-lower alkyl group (R'₇) is introduced as illustrated in Flowsheet O below via the bromomagnesium enolate (CXXV). This novel and useful intermediate is obtained by conjugate addition of the 1-alkenyl Grignard reagent [(CXXIII) + (CXXIV)], preferably prepared at about 35° C, to the cycloalkenone (CXXII) in the presence of a catalyst such as the tri-n-butylphosphine cuprous iodide complex as described hereinabove in connection with Flowsheets G and H. It is also possible to utilize for these purposes in an analogous manner the magnesio enolate (CXXVIII) obtained by conjugate addition of Grignard (XLII) to cycloalkenone (XLI) as described hereinabove in connection with Flowsheet F, in which case the 13,14-dihydro derivative of this invetnion are obtained. In Flowsheet O below, n, Z, R₃, R'₃, R'₂, W₂, R₂, Q and X are as hereinabove defined and R'₇ is an alkyl group having up to 3 carbon atoms. When the magnesio enolate (CXXV) is treated with a lower alkyl halide, e.g., methyl iodide, it undergoes alkylation at the 8β-site providing, after deblocking of the 15-oxy group in intermediate (CXXVI), the 8β-alkyl derivative (CXXVII). In the instance of alkyl esters, saponification gives the corresponding carboxylic acids (CCXXVII, R₃ ═OH). The compounds corresponding to (CXXVII) wherein C₁₃ -C₁₄ is a cis-vinylene double bond are preferably prepared by utilizing the vinyl Grignard reagent prepared at temperatures in the range of 70°-75° C., as discussed hereinabove (Flowsheets G and H).

Also obtained from the alkylation of (CXXV) is the 8α-alkyl-8-iso derivative corresponding to (CXXVI), which after deblocking provides the 8α-alkyl-8-iso-products (CXXIX). Usually the 8α-product is formed to a significantly lesser extent than the 8β-product (CXXVI). The 8α and 8β products are seperable from each other by the usual techniques of chromatography. ##STR29##

Application of the 8-alkylation process to the 11-oxy series provides the novel compounds of formula (CXXX), wherein R₁, R₂, R₆, Y and C₁₃ -C₁₄ are as hereinabove defined and wherein R'₇ is an alkyl group having up to 3 carbon atoms, R₈ is selected from the group consisting of hydrogen, lower alkanoyl, tetrahydropyranyl and tri-lower alkylsilyl groups, R₉ is selected from the group consisting of hydroxy, alkoxy having from 1 to 12 carbon atoms, tetrahydropyranyloxy and tri-lower alkyl silyloxy groups, Z₂ is a divalent radical selected from the group consisting of those of the formulae: ##STR30## wherein m, p, R₄ and R₅ are as hereinabove defined; and the moiety ##STR31## when Y is ##STR32## can also be the divalent radical ##STR33## with the proviso that only one unsaturated bond can be directly adjacent to C₁₅ ; and with the second proviso that when R₆ is alkyl then R₁ is hydrogen; and with the third proviso that the groups attached to C₈ may be in the 8β-alkyl (8-iso) configuration: ##STR34##

The novel compounds of formula (CXXX) are also embraced by this invention. The preparation of these compounds may be illustrated by the reaction sequence of Flowsheet P below, wherein R₉, Z₂, W₂, R"₂, R'₇ and R₃ are as hereinabove defined and R'₈ has all the possiblilities defined above for R₈ except that it is not hydrogen. ##STR35##

In accordance with the sequence of Flowsheet P above, treatment of the ether-ester 4-oxycyclopentenone (CXXXI) with the 1-alkylene Grignard reagents [(CXXIII) + (CXXIV)] (see Flowsheet 0) give the bromomagnesio enolate (CXXXII). This operation also results in the introduction of the trans C₁₃ -C₁₄ double bond (as shown in CXXXII), as well as the corresponding compound with the cis-double bond. The trans bond is favored when the Grignard is prepared at lower temperatures, about 35° C.; the cis-bond at higher temperatures, about 70°-75° C. This point is more fully discussed above in connection with Flowsheets G and H. The magnesio enolate (CXXXII) is a key intermediate and when it is treated with a lower alkyl halide, e.g. methyliodide, it undergoes alkylation to give the 8β-lower alkyl derivative (CXXXIII). Deblocking of the 15-hydroxy blocking group (e.g., triphenylmethyl), and of the 11-hydroxy tetrahydropyranyl or trialkylsilyl ether blocking groups as well as of the tetrahydropyranyl or trialkyl silyl esters is accomplished under mild acid conditions, e.g. heating at 45° C. for 3.5 hours in a solvent system consisting of acetic acid:tetrahydrofuran:water (4:2:1). This procedure provides (CXXXV). The compounds of structure (CXXXV) or (CXXXIII) can be converted to 8β-alkyl prostaglandins of the A class (CXXXIV) by treatment with acid or base, a preferred procedure involves treatment in tetrahydrofuran:water (2:1) solvent 0.5N in hydrochloric acid for about seventy hours at ambient temperatures.

The novel compounds of this invention represented by formula (CXXXIV) and related compounds are particularly interesting sunce they represent "stabilized" prostaglandin A types, which cannot rearrange to the biologically relatively inactive prostaglandins of the B series.

Utilization of Grignard (XLII) (see Flowsheet F, hereinabove) in the sequence of Flowsheet P provides the compounds of (CXXX) wherein C₁₃ -C₁₄ is ethylene. Provided there are no other double bonds in the molecule these substances can also be obtained by catalytic hydrogenation of the compounds represented by formula (CXXXV).

The alkylation process described above for Flowsheets O and P also gives the corresponding 8α-alkyl derivatives which are separable from the 8β-alkyl isomer by chromatography. Thus, for example, in Flowsheet O treatment of enolate (CXXV) with R'₇ I gives not only the 8β-alkyl product (CXXVI) as shown, but there also is obtained the 8α-alkyl derivative (CXXXVI) shown below. In Flowsheet P, alkylation of enolate (CXXXII) also provides, in addition to (CXXXIII) shown, the 8α-alkyl-8-iso product (CXXXVII), shown below. These 8α-alkyl-8-iso derivatives can be deblocked and carried through the same series of transformation shown for the 8β-derivatives (CXXVI) and (CXXXIII) in Flowsheets O and P, respectively. These novel 8α-alkyl-8-iso derivatives and their transformation products are also a part of this invention, as are the key intermediate enolates represented by structures (CXXV) and (CXXXII). ##STR36##

The novel compounds of the present invention have potential utility as hypotensive agents, anti-ulcer agents, agents for the treatment of gastric hypersecretion and gastric erosion, bronchodilators, antimicrobial agents, anticonvulsants, abortifacients, agents for the induction of labor, agents for the induction of menses, fertility-controlling agents, central nervous system regulatory agents, analgesic agents, salt and water-retention regulatory agents, diuretics, fat metabolic regulatory agents, serum-cholesterol lowering agents, anti-inflammatory agents and as agents for the inhibition of platelet aggregation, and for the treatment of periodontal disease, glaucoma, uveitis, sickle cell anemia and psoriasis. Certain of the novel compounds of this invention possess utility as intermediates for the preparation of other of the novel compounds of this invention.

The compounds of this invention provide protection against the ulcerogenic properties of indomethacin. This assay was carried out in the following manner.

Rats were starved for 48 hours (water was given ad libitum). Indomethacin (20 mg./kg. of body weight) was administered by the subutaneous route and one-half the dose of the test compound was administered by gavage at the same time. After 3 hours, the second half of the test compound was administered also by Gavage. Five hours after the administration of indomethacin the animals were decapitated and the stomachs removed. The stomachs were washed with distilled water, blotted on gauze, cut along the larger curvature, and the contents rinsed with distilled water. The stomachs were spread out, pinned on a cork and visualized under magnifying glass for ulcers. The criteria for scoring of ulcers was as previously reported. [Abdel-Galil et al. Brit. J. Pharmac. Chemotherapy 33:1-14 (1968)].

Score

0 -- Normal stomach

1 -- Petechial hemorrhage or pin point ulcer

2 -- 1 or 2 small ulcers

3 -- Many ulcers, a few large

4 -- Many ulcers, mainly large

Control animals treated with indomethacin but not test compound consistently give scores of about 3.0-3.5. Control animals treated with neither indomethacin nor test compound give scores of about 0.5-0.8. The results obtained in this assay with typical compounds of the present invention are set forth in Table 1 below. Compounds producing a score of 2.5 or lower are considered to be active.

                  TABLE I                                                          ______________________________________                                                    Total Oral                                                                     dose; mg./kg.                                                                  of body    Score                                                    Compound     weight       Treated   Control                                    ______________________________________                                         9-oxo-15-hydroxy-                                                              16-ethyl-13-trans-                                                             prostenoic acid                                                                             25           1.7       3.2                                        9-oxo-15-hydroxy-                                                              13-cis-prostenoic                                                              acid         100          1.3       3.0                                        9-oxo-15-hydroxy-                                                              2-ethyl-13-trans-                                                              prostenoic acid                                                                             50           2.2       3.0                                        9-oxo-8β-methyl-                                                          15-hydroxy-13-                                                                 trans-prostenoic                                                               acid         12.5         2.0       3.0                                        9-oxo-3-thia-15-                                                               hydroxy-13-trans-                                                              prostenoic acid                                                                             25           1.8       3.2                                        9-oxo-3-thia-15-                                                               epi-hydroxy-13-                                                                trans-prostenoic                                                               acid         25           2.3       3.2                                        ______________________________________                                    

The novel compounds of the present invention are also effective inhibitors of gastric acid secretion and of ulcer development in experimental animals, and thus are potentially valuable as agents for the control of gastric acid secretion and of gastric erosion and as anti-ulcer agents. Gastric acid secretion inhibitory action is usually measured by the "Shay rat" procedure .sup.(1,2) with some modifications as follows.

The rats (male, CFE strain) were starved for 48 hours (water was given ad libitum) to permit evacuation of stomach contents. On the morning of the experiment, under ether anesthesia, the abdominal region was shaved and a midline incision (1-1 1/2 inch) was made with a scapel. With the help of a closed curved hemostate the duodenum was picked up. Upon getting the duodenum into view, fingers were used to pull the stomach through the opening, the stomach was then gently manipulted with fingers to rid the stomach of air and residual matter which were pushed through the pylorus. Two-5 inch sutures were drawn under the pyloric-duodenal puncture. A ligature, at the juncture was formed with one of the threads. The second ligature was also formed but not tightened.

The test compound or the vehicle, usually 1 ml./mg. body weight, were injected into the duodenum as close as possible to the first ligature. After injection the second ligature was tightened below the injection site to minimize leakage. The stomach was placed back through the opening into the abdominal cavity, the area of incision was washed with saline and the incision was closed with autoclips. (Occasinally, instead of an intraduodenal injection, animals were dosed by the oral or subcutaneous route. In the latter case, dosing was done 30 to 6 minutes before the operation).

Three hours later, the rats were decapitated and exanguinated, taking care that blood did not drain into the esophagus. The abdominal cavity was exposed by cutting with scissors and the esophagus close to the stomach was clamped off with a hemostat, the stomach was removed by cutting above the hemostat (the esophagus was cut) and between the two sutures. Extraneous tissue was removed, the stomach washed with saline and blotted on gauze. A slit was carefully made in the stomach which was held over a funnel and the contents were collected in a centrifuge tube. The stomach was further cut along the outside edge and turned inside out. Two ml. H₂ O were used to wash the stomach contents into the respective centrifuged tube. The combined stomach contents and wash were then centrifuged out for 10 minutes in the International Size 2 Centrifuge (setting at 30). The supernatant was collected, volume measured and recorded, 2 drops of a phenolphthalein indicator (1% in 95% ethanol) were added and the solution was titrated with 0.02N NaOH (or with 0.04N NaOH when large volumes of stomach contents were encountered) to pH 8.4 (because of usual coloring of the stomach contents, phenolphthalein was only used to permit visual indication that the end point was near) and the amount of acid present was calculated.

Compounds inducing inhibition of gastric acid secretion of 20% or more were considered active. In a representative operation, and merely by way of illustration, the results obtained with this assay with a typical compound of the present invention are given in Table 2, below.

                  TABLE 2                                                          ______________________________________                                                         Intraduodenal                                                                  dose, mg./kg.  Percent                                         Compound        of body weight Inhibition                                      ______________________________________                                         9-oxo-15-hydroxy-                                                              3,3-dimethyl-13-                                                               trans-prostenoic                                                               acid            100            51                                              ______________________________________                                    

Bronchodilator activity was determined in guinea pigs against bronchospasms elicited by intravenous injections of 5-hydroxytryptamine, histamine or acetycholine by the Konzett procedure. [See J. Lulling, P. Lievens, F. El Sayed and J. Prignot, Arzeimittel-Forschung, 18 995 (1968).]

In the Table which follows bronchodilator activity for representative compounds of this invention against one or more of the three spasmogenic agents is expressed as an ED₅₀ determined from the results obtained with three logarithemic cumulative intravenous doses.

                  TABLE 2A                                                         ______________________________________                                         Bronchodilator Activity (Konzett Assays)                                       ED.sub.50, mg./kg.                                                                       Spasmogenic Agent                                                                5-hydroxy-                                                         Compound    tryptamine histamine   choline                                     ______________________________________                                         9-oxo-15-hy-                                                                   droxy-16-ethyl-                                                                13-trans-pro-                                                                              --         81.3 × 10.sup.-6                                                                     --                                          stenoic acid                                                                   9-oxo-15-hy-                                                                   droxy-13-cis-                                                                              106 × 10.sup.-6                                                                     81.3 × 10.sup.-6                                                                     320 × 10.sup.-6                       prostenoic                                                                     acid                                                                           9-oxo-15-hy-                                                                   droxy-2-ethyl-                                                                             329 × 10.sup.-6                                                                     145 × 10.sup.-6                                                                      533 × 10.sup.-6                       13-trans-pro-                                                                  stenoic acid                                                                   9-oxo-15-hy-                                                                   droxy-16-pro-                                                                  stynoic acid                                                                               50.8 × 10.sup.-6                                                                    92.6 × 10.sup.-6                                                                     320 × 10.sup.-6                       ______________________________________                                    

This invention will be described in greater detail in conjunction with the following specific examples. In these examples it is to be noted that Example 724 follows directly after Example 699.

In the examples which follow reference to 15-hydroxy or 15-oxy derivatives, unless otherwise indicated is inclusive of both the 15-epi and 15-normal racemates. In addition, all possible antipodes resulting from asymetry at C₈, C₁₂ and elsewhere in the prostenoic acid molecule are included.

EXAMPLE 1 Preparation of 2-carbalkoxy(methyl/ethyl)-2-(4-carbethoxybutyl)-cyclopentan-1-one

To a stirred solution of the sodium cyclopentanone carboxylate enolate in dimethoxyethane, prepared from 187 g. (1.248 moles) of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters, 52.4 g. (1.248 moles) sodium hydride (57.2% in mineral oil) and 1.6 1. of dimethoxyethane, is added dropwise 309 g. (1.212 moles) of ethyl 5-iodovalerate. The reaction mixture is stirred and heated at reflux for 18 hours. The mixture is cooled and filtered. The solvent is removed from the filtrate by evaporation and the residue is poured into dilute hydrochloric acid and extracted with ether. The combined extracts are washed with water and saline, dried over magnesium sulfate and evaporated to give an oil. The oil is distilled under reduced pressure to give 274 g. of a light yellow oil, b.p. 140°-143° C. (0.17 mm).

EXAMPLE 2 Preparation of 2-(4-carboxybutyl)cyclopentan-1-one

A stirred mixture of 274 g of 2-carbalkoxy (mixed methyl and ethyl esters)-2-(4-carbethoxybutyl)cyclopentan-1-one (Example 1), 600 ml. of 20% hydrochloric acid and 325 ml. of acetic acid is heated at reflux for 20 hours. Solution occurs in approximately 1/2 hour. The solution is cooled and diluted with water and extracted with ether. The combined extracts are washed with saline and dried over magnesium sulfate and evaporated. The residue is evaporated twice with toluene to give 144 g. of an oil.

EXAMPLE 3 Preparation of 2-(4-carbethoxybutyl)cyclopentan-1-one

A stirred solution of 124 g. (0.673 mole) of 2-(4-carboxybutyl)cyclopentan-1-one (Example 2), 800 ml. of ethanol and 1 g. of p-toluenesulfonic acid monohydrate is heated at reflux for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The ether solution is washed with saline, dilute sodium bicarbonate solution and again with saline, dried over magnesium sulfate and evaporated. The oil is distilled under reduced pressure to give 149 g. of a colorless oil, b.p. 106°-109° C. (0.23 mm).

EXAMPLE 4 Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)-cyclopentan-1-one

In the manner described in Example 1, treatment of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters) with sodium hydride in dimethoxyethane followed by ethyl 4-iodobutyrate gives a yellow oil, b.p. 136°-137° C. (0.16 mm).

EXAMPLE 5 Preparation of 2-(3-carboxypropyl)cyclopentan-1-one

In the manner described in Example 2, treatment of 2-carbalkoxy(mixed methyl and ethyl esters)-2-(3-carbethoxypropyl)cyclopentan-1-one (Example 4) with a 20% hydrochloric acid and acetic acid mixture gives a yellow oil.

EXAMPLE 6 Preparation of 2-(3-carbethoxyropyl)cyclopentan-1-one

In the manner described in Example 3, treatment of 2-(3-carboxypropyl)cyclopentan-1-one (Example 5) with p-toluene-sulfonic acid monohydrate in ethanol gives a colorless oil, b.p. 93° C. (0.10 mm).

EXAMPLE 7 Preparation of ethyl and methyl 2-(6-carbethoxyhexyl)-1-cyclopentanon-2-carboxylate

In the manner described in Example 1, ethyl and methyl 2-cyclopentanone carboxylate is reacted with ethyl 7-bromoheptanoate to furnish the subject product, b.p. 147° C (0.09 mm).

EXAMPLE 8 Preparation of 2-(6-carboxyhexyl)cyclopentan-1-one

In the manner described in Example 2, ethyl and methyl 2-(6-carbethoxyhexy)-1-cyclopentanone-2-carboxylate (Example 7 ) is hydrolyzed to furnish the subject product, b.p. 143° C. (0.05 mm).

EXAMPLE 9 Preparation of 2-(6-carbethoxyhexyl)cyclopentan-1-one

In the manner described in Example 3, 2-(6-carboxyhexyl)cyclopentan-1-one (Example 8) is esterified to furnish the subject product, b.p. 110° C. (0.03 mm).

EXAMPLE 10 Preparation of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-one

A stirred solution of 100 g of 2-(6-carbethoxyhexyl)-cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (I.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and hexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distilltion of the residual oil give 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm).

EXAMPLE 11 Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-one

In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonci acid monohydrate gives a yellow oil, b.p. 8°-103° C. (0.35 mm).

EXAMPLE 12 Preparation of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-one

In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110° C. (0.37 mm).

EXAMPLE 13 Preparation of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of 50 g. of 1-acetoxy-2-(6-carbethoxyhexyl)cyclopent-1-one (Example 10) in 150 ml. of chloroform, 200 ml. of water and 18.8 g. of calcium carbonate, cooled in an ice bath, is added dropwise over a period of about 30 minutes, a solution of 30 g. of bromine in 50 ml. of carbon tetrachloride. After stirring for an additional 45 minutes the chloroform layer is separated and washed successively with dilute sodium thiosulfate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure.

The residual oil is dissoled in 50 ml. of N,N-dimethylformamide and added to a mixture of 33 g. of lithium bromide and 32 g. of lithium carbonate in 375 ml. of N,N-dimethylformamide, previously dried by refluxing with 375 ml.of benzene under a Dean-Stark apparatus followed by distillation of the benzene. The mixture is stirred at the reflux temperature for 30 minutes, then cooled and poured into 850 ml. of ice-cold water. The resulting mixture is acidified (cautiously) with 4N hydrochloric acid and extracted with ether three time. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure to afford 41.5 g. of an amber oil. In order to convert any isomeric material to the desired product, 42.5 g. of the above material is treated with 0.500 g. of p-toluenesulfonic acid monohydrate in 450 ml. of absolute alcohol at the reflux temperature for 18 hours. The solution is taken to dryness under reduced pressure. The resulting gum is dissolved in ether and washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness under reduced pressure. The residual oil is distilled to give 30.2 g. of product; b.p. 118° C. (0.05 mm); λ_(max) ^(MeOH) 229 μ(E9950); λ_(max) 5.75, 5.85, 6.15, 8.45 μ; vapor phase chromatography shows 99% product, containing 1% 2-(6-carbethoxyhexyl)cyclopentan-1-one.

This product can be purified by the following procedure. A mixture of 120 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, containing approximately 5% of the saturated analogue, and 7.67 g. (10 mole percent) of p-carboxyphenylhydraxzine in 400 m. of absolute ethanol is stirred at ambient temperatures for 18 hours and is then refluxed for 1 hours. The mixture is cooled, the solvent is evaporated, and the residue is taken up into 150 ml. of chloroform and passed through a column of 450 g. of aluminum oxide (Merck). The filtrate is evaporated to yield a colorless oil containing <0.5% of the saturated impurity.

EXAMPLE 14 Preparation of 2-(3-carbethoxypropyl)cyclopent-2-en-1-one

In the manner described in Example 13, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclopent-1-one (Example 11) followed by dehydrobromiation of lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 15 Preparation of 2-(4-carbethoxybutyl)cyclopent-2-en-1-one

In the manner described in Example 13, treatment of 1-acetoxy-2-(4-carbethoxybutyl)cyclopent-1-eme (Example 12) with bromine and subsequent treatment of the brominated product with a mixture of lithium bromide and lithium carbonate in N,N-dimethylformamide is productive of the subject compound. Treatment of this product with p-carboxyphenylhydrazine by the procedure of Example 13 furnishes a product which contains less than 0.5% of the corresponding saturated ketone.

EXAMPLE 16 Preparatin of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene

To a mixture of 35.97 g. (0.151 mole) of 2-(6-carbethoxyhexyl)-2-cyclopentenone (Example 13) and 15.0 g. (0.180 mole) of methoxyamine hydrochloride in 300 ml. of absolute ethanol is added 25 ml. of pyridine and the resulting solution is stirred for 20 hours at ambient temperatures. The solvent is evaporated and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and the solvent is evaporated to yield an oil. Distillation yields 38.7 g. of a colorless oil, b.p. 115°-118° C. (0.075 mm). IR (film); 1740, 1627, 1053, 890 cm^(-l). λ_(max) (MeOH) 243 (13,000). NMR δ (CDCl₃); 3.89.

EXAMPLE 17 Preparation of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene

To an ice cooled solution of 34.10 g. (0.128 mole) of 1-methoximino-2-(6-carbethoxyhexyl)-2-cyclopentene (Example 16) in 200 ml. of benzene under nitrogen is added dropwise 225 ml. of a 25% solution of diisobutyl aluminum hydride in hexane. The resulting solution is stirred for 2 hours at 0°-5° C. , poured onto ice and dilute hydrochloric acid, and the aqueous phase is saturated with sodium chloride. The organic phase is separated, washed with saturated brine, dried (Na₂ SO₄), and evaporated to yield an oil. The latter is dissolved in 100 ml. of hot hexane and cooled to yield 24.3 g. of crystals, m.p. 62°-64° C. IR (KBr) 3260, 1630, 1059, 893 cm⁻¹. λ_(max) 243 (14,200). NMR (CDCl₃) δ; 2.37

EXAMPLE 18 Preparation of 1-methoximino-2-(7-p-toluenesulfonyloxyheptyl)-2-cyclopentene

To a solution of 5.00 g. (0.0222 mole) of 1-methoximino-2-(7-hydroxyheptyl)-2-cyclopentene (Example 17) in 50 ml. of dry pyridine at 0° C. is added 8.45 g. (0.0444 mole) of p-toluenesulfonyl chloride and the resulting solution is chilled at 5° C. overnight. The mixture is partitioned between 300 ml. of ice water and diethyl ether. The organic phase is washed with 1:1 ice cold hydrochloric acid, cold water, and cold saturated brine, dried (NaSO₄ /K₂ CO₃), and evaporated under reduce dpressure at room temperature to yield an oil. The latter is dissolved in 600 ml. of hexane, treated with 0.5 g of Darco, filtered and evaporated to yield 7.7 g of a colorless oil. IR (film) 1600, 1192, 1182, 1053, 890 cm⁻¹. λ_(max) (MeOH) 228 and 243.

EXAMPLE 19 Preparation of 1-methoximino-2-(8,8-dicarbethoxyoctyl)-2-cyclopentene

To an alcoholic solution of sodiodiethyl malonate, prepared from 0.847 g. (0.0368 g. atoms) of sodium, 100 ml. of absolute ethanol, and 7.05 g. (0.0440 mole) of diethyl malonate is added 7.7 g. of the tosylate of Example 18 and the mixture is refluxed for 2 hours under a nitrogen atmosphere. The mixuture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the orgnic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to yield an oil. The excess diethyl malonate is distilled off under reduced pressure to yield 6.45 g. of a yellowish oil. IR (film) 1775, 1728, 1625, 1054, 890 cm⁻¹.

EXAMPLE 20 Preparation of 1-methoximino-2-(8,8-dicarboxyoctyl)-2-cyclopenten

A mixture of 6.45 g. of the diester of Example 19 and 6.72 g. of potassium hydroxide in 150 ml. of 1:1 aqueous methanol is refluxed for 1 hour, cooled, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with water and saturated brine, dried (Na₂ SO₄) and evaporated to yield a solid. The solid is crystallized from benzene to yield 4.15 g. of tan crystals; m.p. 135°-137° C. (-CO₂).

EXAMPLE 21 Preparation of 1-methoximino-2-(8-carboxyoctyl)-2-cyclopentene

A solution of 3.926 g. (0.0126 mole) of the diacid of Example 20 in 20 ml. of xylene is refluxed for 1.5 hours, cooled, and evaporated to yield a tan solid. IR (KBr) 1720, 1618, 1179, 1050, 986 cm⁻¹.

EXAMPLE 22 Preparation of 2-(8-carboxyoctyl)cycopent-2-en-1-one

The acid methoxime from Example 21 is refluxed for 5 hours with 55 ml. of acetone and 20 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to yield a tan solid. IR (KBr) 1745, 1665 cm⁻¹. λ_(max) (MeOh) 228 (12,600).

EXAMPLE 23 Preparation of 2-(8-carbethoxyoctyl)cyclopent-2-en-1-one

The acid ketone from Example 22 is Fisher esterified with 100 ml. of absolute ethanol, 100 ml. of benzene, and 20 mg. of p-toluenesulfonic acid for 6 hours, cooled, and the solvent is evaporated. The resulting oil is dissolved in 3:1 benzene-ether and the solution is passed through a column of 100 g. of Florisil®. The filtrate is evaporated and the residue is distilled to yield 2.97 g. of a colorless oil, b.p. 137°-139° C. (0.05 Torr).

EXAMPLE 24 Preparation of 2-(4-carbethoxybutyl)-2-cyclopentenone methoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenone (Example 15) with methoxyamine hydrochloride in the manner described in Examples 16 gives an oil, b.p. 107°-109° C. (0.05 mm). IR (film); 1740, 1628, 1050, 885 /cm⁻¹. λ_(max) (MeOH) 243 (13,600).

EXAMPLE 25 Preparation of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime

Treatment of 2-(4-carbethoxybutyl)-2-cyclopentenomethoxime (Example 24) with diisobutyl aluminum hydride in the manner described in Example 17 gives crystals, m.p. 33°-35° C. IR (KBr) 3420, 1630, 1050, 886 cm⁻¹. λ_(max) ^(MeOH) 243 (12,020).

EXAMPLE 26 Preparation of 2-(5-p-toluenesulfonyloxypentyl)-2-cyclopentenone methoxime

Treatment of 2-(5-hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm⁻¹.

EXAMPLE 27 Preparation of 2-(6,6-dicarbethoxyoctyl)-2-cyclopentenone methoxime

To a solution of sodio diethyl ethylmalonate, prepared from 1.63 g. (0.0387 mole) of sodium hydride in mineral oil (57.2%), 100 ml. of ethylene glycol dimethyl ether and 8.5 g. (0.0452 mole) of ethyl diethyl malonate, is added 7.5 g. of tosylate from Example 26 in 20 ml. of ethylene glycol dimethyl ether and the mixture is refluxed for 3 hours and then allowed to stand at room temperature for 18 hours under nitrogen atmosphere. The reaction mixture is filtered and most of the solvent is removed. The mixture is partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with water and saturated brine, dired (MgSO₄), and evaporated to yield an oil. The excess ethyl diethyl malonate is distilled off under reduced pressure to yield 6.7 g. of a yellow oil. IR (film ) 1755, 1728, 1627, 1050, 885 cm⁻¹.

EXAMPLE 28 Preparation of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime

Treatment of 2-(6,6-dicarbethoxyoctyl)-2cyclopentenone methoxine (Example 26) with potassium hydroxide, and 1:1 aqueous methanol in the manner described in Example 20 gives a light yellow oil.

EXAMPLE 29 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime

In the manner described in Example 21, treatment of 2-(6,6-dicarboxyoctyl)-2-cyclopentenone methoxime (Example 28) with xylene at reflux for 18 hours gives a yellow oil.

EXAMPLE 30 Preparation of 2-(6-carboxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone methoxime (Example 29) with acetone and 2N hydrochloric acid in the manner described in Example 22 gives a light yellow oil.

EXAMPLE 31 Preparation of 2-(6-carbethoxyoctyl)-2-cyclopentenone

Treatment of 2-(6-carboxyoctyl)-2-cyclopentenone (Example 30) with thionyl chloride and then treatment of the acid chloride with ethanol in the usual manner gives an amber oil. The oil is placed on a magnesia-silica gel column and eluted with 3:1 benzene:ether. The solvent is removed and the residue is distilled, b.p. 122°C. (0.06 mm).

EXAMPLE 32 Preparation of diethyl 1,1-dimethyl-5-tetrahydropyranylpentylmalonate

To 486 mg. (0.02 g.-atoms) of magnesium in 5 ml. of toluene containing one molar equivalent of tetrahydrofuran per equivalent of magnesium and one percent iodine (calculated in weight of magnesium) is added dropwide 3.86 g. (0.02 mole) of 4-chloro-1-tetrahydropyranyloxybutane over a period of one hour with stirring, under nitrogen at 70° C. The reaction mixture is stirred at 70° C. for four hours. This reagent is then added dropwise to 3 g. (0.015 mole) of ethyl isopropylidenemalonate in 40 ml. of tetrahydrofuran containing 392 mg. of tetrakis [iodo(tri-n-butylphosphine)copper (I)] and stirred at room temperature for 2 hours. The reaction mixture is poured into cold dilute hydrochloric acid and extracted with ether. The ether extract is dried over magnesium sulfate and concentrated to give 5.92 g. of subject product as an oil.

EXAMPLE 33 Preparation of diethyl 1,1-dimethyl-5-hydroxypentylmalonate

A solution of 3.5 g. (0.01 mole) of diethyl 1,1-dimethyl-5-tetrahydrofuranyloxypentylmalonate in 70 ml. of ethanol containing 3 ml. of hydrochloric acid is allowed to stir at room temperature for 18 hours. The solution is concentrated, diluted with water, and extracted with ether. The ether extract is washed with water dried over magnesium sulfate and concentrated to give 3.262 g. of a light yellow oil. The oil is purified by distillation, b.p. 116°-117° C. (0.05 mm).

EXAMPLE 34 Preparatin of 3,3-dimethyl-7-hydroxyheptanoic acid

A mixture of 32 g. (0.117 mole) of diethyl 1,1-dimethyl-5-hydroxypentylmalonate, 25 g. of potassium hydroxide and 600 ml. of methanol-water (1:1) is heated at reflux for 8 hours and then allowed to stand at room temperature for 18 hours. The methanol is removed, diluted with water and the reaction mixture is acidified with concentrated hydrochloric acid. The mixture is extracted with ether. The extract is washed with water and saline, dried over anhydrous magnesium sulfate and concentrated to give 27 g. of 1,1-dimethyl-5-hydroxypentylmalonic acid. This crude oil is dissolved in 200 ml. of bis-(2-methoxyethyl)ether and is heated at reflux for 4 hours and then allowed to stand at room temperature overnight. The solvent is removed and the reaction mixture is diluted with water and extracted with ether. The organic solution is washed with saline, dried over magnesium sulfate and concentrated to give 18 g. of product as an oil.

EXAMPLE 35 Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3.484 g.(0.02 mole) of 3,3-dimethyl-7-hydroxyheptanoic acid in 25 ml. of chloroform containing 3 drops of dimethylformamide is added 5.8 ml. (0.08 mole) of thionyl chloride and the solution is then heated at reflux for 3-4 hours. The solution is concentrated to give the intermediate 3,3-dimethyl-7-chloro-1-heptanoyl chloride. The acid chloride is dissolved in a minimum amount of benzene and added slowly to 20 ml. benzene, 10 ml. of ethanol and 2.65 ml. of collidine. The solution is heated at reflux for one hour and then concentrated. The residue is dissolved in ether, washed with water, dilute sodium bicarbonate solution and saline. The organic solution is dried over magnesium sulfate and concentrated to give 3.57 g. of product as a yellow oil.

EXAMPLE 36 Preparation of ethyl 3,3-dimethyl-7-iodoheptanoate

To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and centrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87° C. (0.18 Torr).

EXAMPLE 37 Preparation of 2-carbalkoxy(methyl/ethyl)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one

This compound is prepared by treatment of sodio cyclopentanone carboxylate enolate with ethyl 3,3-dimethyl-7-idoheptanoate by the procedure described in Example 1.

EXAMPLE 38 Preparation of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one

This compound is prepared by decarbalkoxylation of 2-carbalkoxy (mixed methyl and ethyl ester)-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one by the procedure described in Example 39

EXAMPLE 29 Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one

Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure described in Example 3 is productive of the subject compound.

EXAMPLE 40 Preparation of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene

This compound is prepared from 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentan-1-one and acetic anhydride by the process described in Example 10.

EXAMPLE 41 Preparation of 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

This compound is prepared from 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene via bromination and dehydrobromination according to the procedure described in Example 13.

EXAMPLE 42 Preparation of 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example 16, 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-2-cyclopentenone (Example 14) and methoxyamine hydrochloride.

EXAMPLE 43 Preparation of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene

In the manner described for the preparation of the compound of Example 17, 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene is prepared from 2-(3-carbethoxypropyl)-1-methoximino-2-cyclopentene and diisobutylaluminum hydride.

EXAMPLE 44 Preparation of 2-(6-carbethoxy-5-oxahexyl)-b 1-methoximino-b 2-cyclopentene

To an ice cold solution of 4.833 g. (0.0266 mole) of 2-(4-hydroxypentane)-1-methoximino-2-cyclopentene in 50 ml. of dry tetrahydrofuran under nitrogen is added 16.7 ml. of 1.6 molar n-butyl lithium in hexane, dropwise. The reaction mixture is stirred for 0.5 hour and then 4.85 g. (0.029 mole) of ethyl bromacetate is added dropwise. The reaction mixture is stirred overnight at room temperature and then reluxed for 1.5 hours. The reaction is cooled and poured into water and extracted several times with ether. The ether extracts are washed with saline, dried over magnesium sulfate, and concentrated. The residue is placed on an alumina column, chloroform being used as a wash solvent. The combined washings are concentrated to dryness to give 4.903 g. of product an a yellow oil.

EXAMPLE 45 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of 2-(6-carbethoxy-5-oxahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

EXAMPLE 46 Preparation of 2-(6-carbethoxy-5-oxahexyl)2-cyclopentenone

In this manner described in Example 23, treatment of 2-(6-carboxy-5-oxahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol produces the subject product as a light yellow oil.

EXAMPLE 47 Preparation of 2-(6-carboxy-5-oxahexyl)-1methoximino-2-cyclopenten

To an ice cold solution of 3.66 g. (0.02 mole) of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene (Example 43) in 50 ml. of 1,2-dimethoxyethane under nitrogen is added dropwise 17 ml. of 1.6 M n-butyl lithium in hexane. The reaction mixture is stirred for half an hour and then the lithium salt of chloroacetic acid, prepared from 1.89 g. (0.02 mole) of chloroacetic acid and 16 ml. of 1.6 M n-butyl lithium in 20 ml. of dimethoxyethane, is added and the reaction mixture is heated at reflux for 48 hours. The solvent is evaporated and the residue is partitioned between ether and water. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The organic phase is washed with water and saturated saline solution, dried (MgSO₄), and evaporated to give 3.35 g. of a yellow oil.

EXAMPLE 48 Preparation of 2-(6-carboxy-5-oxahexyl)-2-cyclopenten-1-one

In the manner described in Example 22, treatment of 2-(6-carboxy-5-oxahexyl)-1-methoximino-2-cyclopentene (Example 47) with acetone and 2N hydrochloric acid at reflux gives the subject compound as a yellow oil.

EXAMPLE 49 Preparation of 1-methoximino-2-(4-methanesulfonyloxybutyl)-2-cyclopentene

To a solution of 1.83 g. (0.01 mole) of 1-methoximino-2-(4-hydroxybutyl)-2-cyclopentene (Example 43) in 10 ml. of mythylene chloride containing 1.52 g. (0.015 mole) of triethylamine is added 1.265 g. (0.011 mole) of methanesulfonyl chloride over a period of 5-10 minutes at -10-0° C. Stirring is continued for 15 minutes and the solution is then washed with cold water, cold 10% hydrochloric acid, cold sodium bicarbonate solution, and cold saline solution. The organic phase is dried (MgSO₄) and concentrated to give an oil which solidifies upon cooling. Crystallization from ether-petroleum ether (30°-60° C.) gives 1.797 g. of white crystals, m.p. 67°-68° C.

EXAMPLE 50 Preparation of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene

A mixture of 2.75 g. (0.01 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) and 1.47 g. (0.03 mole) of sodium cyanide in 20 ml. of dry N,N-dimethylformamide is heated at 65°-70° C. for 3 hours. The cooled reaction mixture is poured into water and extracted with diethyl ether. The organic phase is washed with water and saturated saline solution, dried (MgSO₄), and evaporated to give 1.89 g. of a light yellow oil.

EXAMPLE 51 Preparation of 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene

A mixture of 1.89 g. (0.0092 mole) of 1-methoximino-2-(5-cyanopentyl)-2-cyclopentene (Example 50) and 1 g. (0.025 mole) of sodium hydroxide in 50 ml. of 1:1 aqueous-ethanol is refluxed for 48 hours, cooled, and partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with diethyl ether, and the organic phase is washed with water and saturated saline solution, dried (MgSO₄), and evaporated to give 1.86 g. of a yellow oil.

EXAMPLE 52 Preparation of 2-(5-carboxypentyl)-2-cyclopentenone

A solution of 1.86 g. (0.00825 mole) 1-methoximino-2-(5-carboxypentyl)-2-cyclopentene (Example 51) in 44 ml. of acetone and 13.1 ml. of 2N hydrochloric acid is refluxed for 5 hours. The solvent is partially evaporated and a solid precipitates and is collected. The residue is extracted with diethyl ether and the organic phase is washed with saturated saline solution, dried (MgSO₄), and evaporated to yield additional solid. The combined solid material is crystallized from ether/pet ether (30°-60° C°) to yield crystalline material, m.p. 70°-72° C.

EXAMPLE 53 Preparation of 2-(5-carbethoxypentyl)-2-cyclopentenone

A solution of 1.309 g. (0.00668 mole) of 2-(5-carboxypentyl)-2-cyclopentenone (Example 52) and 90 mg. of p-toluenesulfonic acid in 150 ml. of ethanol is refluxed for 18 hours. The solvent is evaporated and the residue is dissolved in ether. The organic phase is washed with water, sodium bicarbonate solution, and saturated saline solution, dried (MgSO₄), and evaporated to give 1.371 g. of a light yellow oil.

EXAMPLE 54 Preparation of 2-(5-acetoxypentyl)-2-carbomethoxy/carbethoxy-cyclopentanone

A mixture of sodiocyclopentanone carboxylate, prepared from 1200 g. (8.0 moles) of cyclopentanone carboxylate (methyl and ethyl esters) and 200 g. (8.3 moles) of mineral oil free sodium hydride in 10 1. of 1,2-dimethoxyethane, 1320 g. (8.0 moles) of 5-chloro-1-amyl acetate [M.E. Synerhold, Journ. Amer. Chem. Soc., 69, 2681 (1947)], and 1200 g. (8.0 moles) of sodium iodide is refluxed under nitrogen for 18 hours. The mixture is cooled, concentrated to 4 1. and partitioned between dilute hydrochloric acid and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO₄), and evaporated to yield 1920 g. of an oil.

EXAMPLE 55 Preparation of 2-(5-hydroxypentyl)cyclopentanone/2-(5-acetoxypentyl)-cyclopentanone

A mixture of 4,500 g. (16.2 moles) of 2-(5-acetoxypentyl)-2-carbomethoxy/carboethoxy-cyclopentanone (Example 54), 2.2 1. of glacial acetic acid, 1 1. of concentrated hydrochloric acid, and 1 1. of water is refluxed for 18 hours, cooled, and partitioned between saturated brine and benzene. The organic phase is washed with saturated brine, dried (MgSO₄), and evaporated in vacuo to yield 3155 g. of an oil.

EXAMPLE 56 Preparation of 1-acetoxy-2-(5-acetoxypentyl)-1-cyclopentene

A solution of 400 g. (2.04 moles) of a mixture of 2-(5-hydroxypentyl)cyclopentanone and 2-(5-acetoxypentyl)cyclopentanone (Example 55) and 4.0 g. of p-toluenesulfonic acid monohydrate in 11. of acetic anhydride is refuluxed at a rate to maintain a steady distillation of acetic acid from the reaction through a helix-packed fractionation column. The reaction is continued with the addition of acetic anhydride to maintain a constant volume until complete conversion of starting materials to product is evident. The mixture is cooled and partitioned between 2 l. of hexane and 3 1. of cold water contining solid sodium bicarbonate to maintain a neutral pH. The organic phase is washed with saturated brine, dried (MgSO₄), and evaporated to yield 452 g. of an oil.

EXAMPLE 57 Preparation of 2-(5-acetoxypentyl)-2-cyclopentenone

To a well stirred mixture of 405 g. (4.05 moles) of calcium carbonate, 3 1. of water, and 2.51. of chloroform cooled to 5° C. is added simultaneously 1016 g. (4.0 moles) of 1-acetoxy-2-(5-acetoxy-pentyl)-1-cyclopentene (Example 56) and a solution of 648 g. (4.05 moles) of bromine in 500 ml. of carbon tetrachloride at a rate of maintain a temperature below 10° C. The mixture is stirred for half an hour after addition of the reagents and the phases are then separated. The organic phase is washed with 2% sodium thiosulfate solution, water, and saturated brine, dried (MgSO₄), and evaporated in vacuo to an oil. The oil is immediately added to a refluxing slurry of 500 g. (5.0 moles) of calcium carbonate in 2.5 1 of N,N-dimethylacetamide under nitrogen and the mixture is then refluxed for thirty-minutes. The mixture is cooled, filtered, and partitioned between water and diethyl ether. The organic phase is washed with water and saturated brine, dried (MgSO₄), and evaporated to yield 757 g. of an oil, b. p. 116°-118° C. (0.25 mm.).

EXAMPLE 58 Preparation of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene

In the manner described for Example 16, 2-(5-acetoxypentyl)-2-cyclopentenone (Example 57) is treated with methoxyamine hydrochloride in pyridine and ethanol to yield the subject compound, b.p. 010°-103° C. (0.20 mm.).

EXAMPLE 59 Preparation of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene

A mixture of 74 g. (0.22 mole) of 1-methoximino-2-(5-acetoxypentyl)-2-cyclopentene (Example 58) and 56 g. (1.0 mole) of potassium hydroxide in 300 ml. of 1:1 aqueous methanol is refluxed for 2 hours and then cooled. The solvent is partially removed in vacuo and the residue is partitioned between saturated brine and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO₄), and evaporated to yield an oil which crystallized, m.p. 35° -36° C.

EXAMPLE 60 Preparation of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene

To a cold solution of 9.85 g. (0.05 mole) of 1-methoximino-2-(5-hydroxypentyl)-2-cyclopentene (Example 59) and 7.6 g. (0.075 mole) of triethylamine in 100 ml. of methylene chloride at -10C. is added 6.3 g. (0.055mole) of methanesulfonyl chloride at a rate to maintain a temperature of -10° to 0° C. The mixture is then stirred for 15 minutes and then poured into ice water. The organic phase is washed with cold 10% hydrochloric acid, cold saturated sodium bicarbonate solution, and cold saturated brine, dried (MgSO₄), and evaporated to yield a solid, m.p. 78° -80° C.

EXAMPLE 61 Preparation of 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene

To a suspension of sodiodiethylmalonate in 1,2-dimethoxyethane, prepared from 248 g. (1.55 moles) of diethyl malonate and 17.2 g. (0.95 mole) of mineral oil free sodiumhydride in 11. of 1,2-dimethoxyethane under nitrogen, is added 170 g. (0.62 mole) of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) in 1.51. of 1,2-dimethoxyethane and the mixture is refluxed for 5 hours. The mixture is cooled, filtered, and the solvent is evaporated. The residue is partitioned between cold dilute hydrochloric acid and water, and the organic phase is washed with saturated brine, dried (MgSO₄), and evaporated to remove solvent and excess diethyl malonate to yield 209 g. of an oil.

EXAMPLE 62 Preparation of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene

In the manner described in Example 20, 1-methoximino-2-(6,6-dicarbethoxyhexyl)-2-cyclopentene is treated with potassium hydroxide in 1:1 aqueous methanol and then hydrochloric acid to yield the desired compound as crystals from diethyl ether, m.p. 110° -115° C.

EXAMPLE 63 Preparation of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene

A solution of 141 g. (0.50 mole) of 1-methoximino-2-(6,6-dicarboxyhexyl)-2-cyclopentene in 500 ml. of bis-(2-methoxyethyl) ether is refluxed for 2 hours, cooled, and evaporated, to yield an oil. The latter is crystallized from hexane to yield 92 g. of solid, m.p. 70° -72° C.

EXAMPLE 64 Preparation of 2-(6-carboxyhexyl)-2-cyclopentenone

In the manner described in Example 22, treatment of 1-methoximino-2-(6-carboxyhexyl)-2-cyclopentene (Example 63) with acetone and 2N hydrochloric acid at reflux provides the subject compound.

EXAMPLE 65 Preparation of 2-(6-carbethoxyhexyl)-2-cyclopentenone

Fischer estification of 2-(6-carboxyhexyl)-2-cyclopentenone (Example 64) in the manner of Example 23 provides the subject compound.

EXAMPLE 66 Preparation of 1-methoximino-2-(6-fluoro-6,6-dicharbethoxyhexyl)-2-cyclopentene

To a solution of sodiodiethyl fluoromalonate, prepared from 2.062 g. (0.0491 mole) of sodium hydride in mineral oil (57.26), 40 ml. of dry N,N-dimethylformamido and 8.174g. (0.0458 mole) of diethyl fluoromalonate is added dropwise 11.32 g. (0.0413 mole) of 1-methoximino-2-(5-methylsulfonyl-oxypentyl)-2-cyclopentene (Example 60 ) in ml. of N,N-di-methylformamide. The mixture is reluxed for 2 hours under a nitrogen atmosphere. The mixture is concentrated and partitioned between cold dilute hydrochloric acid and diethyl ether, and the organic phase is washed with saturated brine, dried (MgSO₄), and evaporated to yield 13.631 g. (92%) of a yellow oil.

EXAMPLE 67 Preparation of 1-methoximino-2-(6-fluoro,6,6-dicarboxyhexyl)-2-cyclopentene

A mixture of 13.631 g. of the diester of Example 66 and 16 g. of potassium hydroxide in 364 ml. of 1:1 aqueous methanol is refluxed for 5 hours, cooled, concentrated, and is partitioned between water and diethyl ether. The aqueous phase is acidified with hydrochloric acid, extracted with ether, and the organic phase is washed with saturated brine, dried (MgSO₄) and evaporated to yield a solid. The solid is crystallized from diethyl ether petroleum ether (30° -60° C.) to give 10 g. (90%) of white crystals, m.p. 143° -145° C. (-CO₂).

EXAMPLE 68 Preparation of 1-methoximino-2-(6-fluoro-6-carboxyhexyl)-2-cyclopentene

A solution of 10 g. of the diacid of Example 67 in 60 ml. of 2-methoxyethyl ether is refluxed for 7 hours, cooled and evaporated to yield 8.5 g. (95%) of a tan solid. A sample is crystallized from diethyl ether-petroleum ether (30° -60° C.) to give white crystals, m.p. 98° -100° C.

EXAMPLE 69 Preparation of 2-(6-fluoro-6-carboxyhexyl)cyclopent-2-en-1-one

The acid methoxime (8.5 g.) from Example 68 is refluxed for 5 hours with 180 ml. of acetone and 64 ml. of 2N hydrochloric acid. The mixture is cooled, the solvent is evaporated, and the residue is partitioned between water and diethyl ether. The organic phase is washed with saturated brine, dried (MgSO₄) and evaporated to yield 7.4 g. (98%) of a light yellow oil.

EXAMPLE 70 Preparation of 2-(6-fluror-6-carbethoxyhexyl)cyclopent-2-en-1-one

The acid ketone (7.4 g.) from Example 69 is Fisher esterified with 300 ml. of absolute ethanol and 400 mg. of p-toluenesulfonic acid for 18 hours, cooled, and the solvent is evaporated. the resulting oil is dissolved in ether, washed with dilute sodium bicarbonate solution, and saline, dried (MgSO₄), and evaporated to give 7.306 g. (86%) of a light yellow oil.

EXAMPLE 71 Preparation of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(7-p-toluenesulfonyloxy)-2-cyclopentene (Example 18) with sodium cyanide in the manner of Example 50 is productive of the subject compound.

EXAMPLE 72 Preparation of 2-(7-carboxyheptyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of 2-(7-cyanoheptyl)-1-methoximino-2-cyclopentene (Example 71) by the procedure of Example 51 is productive of the subject compound.

EXAMPLE 73 Preparation of 2-(7-carboxyheptyl)-2-cyclopenten-1-one

Hydrolysis of the methoxime of Example 72 with acetone-hydrochloric acid by the procedure of Example 52 is productive of the subject compound.

EXAMPLE 74 Preparation of 2-(7-carbethoxyheptyl)-2-cyclopenten-1-one

Fisher estification of the carboxylic acid of Example 73 by the procedure of Example 53 is productive of the subject compound.

EXAMPLE 75 Preparation of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Treatment of 1-methoximino-2-(5-methanesulfonyloxypentyl)-2-cyclopentene (Example 60) with sodio diethyl phenylmalonate by the procedure of Example 61 is productive of the subject compound.

EXAMPLE 76 Preparation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Alkaline hydrolysis of 2-(6,6-dicarbethoxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 75) by the procedure of Example 20 is productive of the subject diacid.

EXAMPLE 77 Preparation of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene

Decarboxylation of 2-(6,6-dicarboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 76) by the procedure of Example 63 is productive of the subject compound.

EXAMPLE 78 Preparation of 2-(6-carboxy-6-phenylhexyl)-2-cyclopentene-1-one

Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1-methoximino-2-cyclopentene (Example 77) in the manner of Example 69 is productive of the subject ketone.

EXAMPLE 79 Preparation of 2-(6-carbethoxy-6-phenylhexyl)-2-cyclopentene-1-one

Fisher esterification of the carboxylic acid of Example 78 in a manner of Example 70 is productive of the subject keto-ester.

EXAMPLE 80 Preparation of 2-(6-fluoro-6,6-dicarbethocyhexyl)-1-methoximino-2-cyclopentene

An ethanolic solution of sodium ethoxide, prepared from 0.389 g. of sodium and 40 ml. of absolute ethanol, is treated at ambient tempratures with 5.05 g. of 2-(6,6-dicarbethoxyhexyl)-1-methoximino-2-cyclopentene (Example 61). The resulting solution is cooled to -20° C. and then treated with a stream of perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is retreated with 10 ml. of an ethanol solution of sodium ethoxide (from 0.350 g. of sodium) and then with perchloryl fluoride until the mixture becomes neutral. The excess perchloryl fluoride is removed with a stream of nitrogen and the mixture is filtered and evaporated to an oil. The latter is partitioned between ether and water and the organic phase is washed with saturated saline, dried (Na₂ SO₄) and evaporated to afford the subject compound.

EXAMPLE 81 Preparaion of 2-(6-carbo-n-butoxyhexyl)cyclopent-2-en-1-one

A solution of 50 g. of 2-(6-carboxyhexyl)cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966] in 1400 ml. of n-butanol containing 2.7 g. of p-toluenesulfonic acid monohydrate is allowed to stand at room temperature in a stopped flask for about 24 hours. The solution is taken to dryness. The residue is taken up in ether and the ethereal solution is washed several times with saline solution, dried with anhydrous magnesium sulfate, and taken to dryness to afford the subject butyl ester.

EXAMPLES 82-84

Treatment of 2-(6-carboxyhexyl)cyclopent-2-en-1-one by the procedure of Example 81 with the appropriate alcohol affords the esters of the following table.

                  TABLE IV                                                         ______________________________________                                         Ex.  Alcohol    Product Ester                                                  ______________________________________                                         82   isopropanol                                                                               2-(6-carboisopropoxyhexyl)cyclopent-2-                                         en-1-one                                                       83   methanol   2-(6-carbomethoxyhexyl)cyclopent-2-en-                                         1-one                                                          84   1-hydroxy- 2-(6-carbo-n-decyloxyhexyl)cyclopent-2-                             n-decane   en-1-one                                                       ______________________________________                                    

EXAMPLE 85 Preparation of diethyl (5-chloro-1,1-dimethylpentyl)malonate

To magnesium (71 g. 2.92 moles) under 1 1. of ether containing a few crystals of iodine is added dropwise 1-chloro-4-bromobutane (500 g., 2.92 moles) over a period of 30 minutes with stirring under nitrogen. The reaction is maintained at a temperature of 0° C. to 5° C. by immersing in an acetone-Dry Ice bath periodically. After stirring for 30 minutes at room temperaure, the solution is chilled to below 0° C. and is then transferred to a dropping funnel from which it is added dropwise to diethyl isopropylidene malonate (440 g., 2.19 moles) [A.C. Cope and E.M. Hancock, J.A.C.S. 60, 2644 (1938)] dissolved in 1000 ml. of ether containing the tri(n-butyl)phosphine complex of copper (I) iodide (57 g) [G. B. Kaufman and L. A. Teter, Inorganic Synthesis, 7, 9(1963)] at -10° C. with stirring under nitrogen over a period of two hours. After stirring at room temperature for four hours, the reaction mixture is poured into cold dilute hydrochloric acid and is extracted with ether. The combined ether extracts are washed with saline solution, dried over magnesium sulfate, and concentrated in vacuo to give 700 g. of crude amber oil, which is distilled under vacuum to yield two fractions: 212.4 g. with b.p. at 110° C-135° C. at 0.3 mm. and 100.0 g with b.p. at 135° -145° C. at 0.3 mm. The total yield is 312.4 g (49%).

EXAMPLE 86 Preparation of 3,3-dimethyl-7-chloroheptanoic acid

A mixture containing diethyl 5-(5-chloro-1,1-dimethylpentyl)malonate (648 g., 2.22 moles) potassium hydroxide (460 g. and eight liters of 1:1 isopropanol: water is stirred at room temperature overnight. Most of the isopropanol is distilled and the residue is diluted with water, and then carefully acidified with conc. hydrochloric acid. The mixture is extracted with ether and the extracts are washed with water and saline, dried over magnesium sulfate and concentrated in vacuo to give 548 g. of crude oil. The oil is dissolved in three liters of diglyne which is heated under reflux for sixteen hours. About 2.7 1. of solvent is distilled, and the remainder is diluted with water and extracted with ether. The extracts are washed with saline, dried over magnesium sulfate and concentrated in vacuo to give 428 g. of crude oil (99%).

EXAMPLE 87 Preparation of ethyl 3,3-dimethyl-7-chloroheptanoate

To a solution of 3,3-dimethyl-7-chloroheptanoic acid (428 g., 2.21 moles) in 3 l. of chloroform containing 3 ml. of N,N-dimethylformamide is added 500 ml. of thionyl chloride and the resulting solutin is tested under reflux for three hours. The reaction solution then is concentrated in vacuo and the residual acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 1260 ml. of 95% ethanol and 2520 ml. of benzene and 390 ml. of collidine. After heating under reflux for one hour, the solution is concentrated and the residue is dissolved in ether washed with water, dilute sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 415 g. of crude oil, which is distilled under vacuum to yield two fractions 46.6 g. boiling at 75° C (0.3 mm.) and 236.7 g. boiling at 75° -80° C. (0.3 mm). The total yield is 283.3 g.(60 %) and the product is indicated to be 95% pure by g.l.c.

EXAMPLE 88 Preparation of methyl/ethyl 2-(6-carbethoxy-5,5-dimethylhexyl)cyclopentanone-2-carboxylate

Sodium hydride (67 g., 1.55 moles) is placed in a three L. round-bottom flask and to this is added 1.1 liters of glyme from a dropping funnel under nitrogen flow and with stirring. To the resulting grayish mixture is added the 2-carbalkoxycyclopentanone (mixed methyl and ethyl esters) dropwise over a period of 45 minutes with nitrogen flow whilst the temprature is maintained in the range of 40°-55°. Ethyl 3,3-dimethyl-7-chloroheptanoate (283 g., 1.28 moles) and potassium iodide (195 g., 1.32 moles) are added and the mixture is heated at reflux overnight. After most of the solvent is distilled, the residue is made acidic with dilute hydrochloric acid and is then extracted with ether. The ether extracts are washed with water and saline solution, dried over magnesium sulfate, and concentrated in vacuo to 500 g. of crude yellow oil, which is distilled to give 405 g. (94% yield) of oil with b.p. 140°-180° (0.8 mm).

EXAMPLE 89 Preparation of 7-(2-Cyclopentanone)-3,3 dimethylheptanoic acid

Methyl/Ethyl 2-(6-carbethoxy-5,5-dimethylhexyl) cyclopentanone-2-carboxylate (200 g, 0.6 mole), glacial acetic acid (180 ml) and 240 ml. of diluted hydrochloric acid, prepared from 100 ml. of conc. hydrochloric acid and 300 ml. of water, are placed in a 2 1. flask, containing a reflux condenser and a magnetic stirrer. The mixture then is stirred at reflux for 24 hours. The reaction mixture is cooled, 1 L. of water is added and the mixture is extracted several times with benzene. The organic extracts are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to an oil (173.5 g). The oil is rendered basic with sodium hydroxide solution, extracted with benzene and made acidic with hydrochloric acid and rextracted with benzene several time. The benzene layers are combined and washed with water, saturated sodium chloride solution, dried over magnesium sulfate, filtred and concentrated to yield 109.8 g. (78%) of crude oil, which was used without further purification in the next step.

EXAMPLE 90 Preparation of Ethyl 7-(2-Cyclopentanone)-3,3-dimethylheptanoate

To a solution of 7-(2-cyclopentanone)-3,3-dimethylheptanoic acid (45 g., 0.22 mol.) in 285 ml. of chloroform containing three drops of N,N-dimethylformamide is added dropwise 25 ml. of thionyl chloride. The solution is stirred at room temperature for twenty minutes, the solvent is removed at reduced pressure and the residue acid chloride is dissolved in a minimum amount of benzene and added slowly to a solution containing 115 ml. of ethanol, 230 ml. benzene and 30 ml. of collodine. This solution is heated under reflux for fifteen minutes and then concentrated. The residue is dissolved in ether, washed with water, diluted sodium bicarbonate solution and saline solution, dried over magnesium sulfate and concentrated to give 51 g. of crude oil. Distillation gives 40 g. (67%) b.p. 135°-145° (0.1 mm.) of oil.

EXAMPLE 91 Preparation of 1-Acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)-cyclopent-1-ene

A solution of ethyl 7-(2-cyclopentanone)-3,3-dimethylheptanoate (90 g., 0.336 mol.) and p-toluenesulfonic acid (0.94 g.) in 250 ml. of acetic anhydride is heated to boiling under partial reflux, allowing distillate at 118° or less (i.e. acetic acid) to escape thru a Vigreux column equipped with a condenser to collect the distillate. After ten hours 130 ml. of distillate is collected. Another 50 ml. of acetic anhydride is added and the reaction is heated for five more hours; an additional 125 ml. of acetic anhydride is added, the reaction is heated for seven more hours; finally another 50 ml. of acetic anhydride is added and heating is continued for four more hours. The solution is cooled and poured (cautiously) into a cold (0°-5°) mixture of saturated aqueous sodium bicarbonate (400 ml.) and hexane (250 ml.). The resulting cold mixture is stirred for thirty minutes during which time portions of solid sodium bicarbonate are added periodically until carbon dioxide evaluation ceases. The hexane layer is separated and washed with saturated sodium chloride solution until the washings are neutral, dried over magnesium sulfate and treated with Darco decolorizing charcoal for clarification and then evaporated to dryness leaving an amber colored oil (87.5 g., 84%).

EXAMPLE 92 Preparation of 2-(6-Carboxy-5,5-dimethylhexyl)cyclopent-2-en-1-one

To a rapidly stirred mixture of 1-acetoxy-2-(6-carbethoxy-5,5-dimethylhexyl)cyclopent-1-ene (35 g., 0.113 mole) chloroform (95 ml.), water (125 ml.) and calcium carbonate (11.8 g.) cooled in an ice-bath is added dropwise over a period of thirty minutes a solution of bromine (18.8 g.) in carbon tetrachloride (31 ml.). After stirring in the cold for an additional 45 minutes the orange colored chloroform layer is separated and washed with dilute sodium bisulfite and saturated saline solution, dried over magnesium sulfate and taken to dryness in vacuo (bath temperature: 35°-40°) leaving an amber colored oil. A slurry of 100 ml. of N,N-dimethylacetamide and 16.5 g. of CaCO₃ is stirred and heated to reflux under nitrogen flow. The above dried oil is added from a dropping funnel rapidly, maintaining reflux and nitrogen flow for thirty minutes. The cooled reaction mixture is filtered, and the precipitate is washed with ether. The filtrate is poured into two liters ice-cold water and is extracted with ether. The combined extracts and washing is washed with water, saturated saline, treated with decolorizing charcoal, filtered. The solvent evaporated in vacuo to give 24 g. (77%) of subject product.

EXAMPLE 93 Preparation of 4-bromo-2(6-carboxyhexyl)cyclopent-2-en-1-one

A stirred mixture of 35.9 g. (0.171 moles) of 2-(6-carboxyhexyl) cyclopent-2-en-1-one [Bagli et al., Tetrahedron Letters, No. 5, 465 (1966)], 35.0 g. (0.197 moles) of N-bromosuccinimide, and 600 ml. of carbon tetrachloride is refluxed for 35 minutes. The mixture is cooled to 5° C. and filtered. The filtrate is washed with cold water, dried over magnesium sulfate, and taken to dryness to give an oil, λ_(max).^(MeOH) = 225 mμ (8850); νmax. = 1705 (carbonyl groups) and 1625 cm^(-a) (olefin group).

EXAMPLE 94 Preparation of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one

To a stirred solution of 10.6 g. (ca. 34 mmoles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λ_(max).^(MeOH) = 233 mμ (7360); νmax. = 3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm⁻¹ (olefin group).

EXAMPLE 95 Preparation of 4-tetrahydropyranyloxy-2-(6-tetrahydropyranylcarboxyhexyl)cyclopent-2-en-1-one

To a stirred solution of 5.59 g. (24.6 mmoles) of 4-hydroxy-2-(6-carboxyhexyl) cyclopent-2-en-1-one (Example 94) and 20.7 g. (246 mmoles) of dihydropyran in 100 ml. of methylene chloride at 20° C. is added 47 mg. (0.246 mmoles) of p-toluenesulfonic acid monohydrate in one portion. The temperature is maintained at 20°-25° C. by cooling and is stirred for one hour at that temperature. The solution is diluted with 200 ml. of ether and poured into a mixture of 40 ml. of saturated sodium bicarbonate solution, 40 ml. of saturated sodium chloride solution, and 80 ml. of water. The phases are separated, and the aqueous phase is extracted with additional ether. The total extract is washed successively with water and saturated sodium chloride solution, dried over potassium carbonate, and freed of volatile matter by concentration at reduced pressure to give an oil, λ_(max).^(MeOH) = 223 μ (9500); νmax. 1730 (ester carbonyl group), 1705 (ketone carbonyl group), and 1030 cm⁻¹ (tetrahydropyranyloxy groups).

EXAMPLE 96 Preparation of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime

The subject compound is prepared from sodio diethyl methylmalonate and 2-(5-methanesulfonyloxypentyl)-2-cyclopentenone methoxime (Example 60) by the procedure described in Example 61.

EXAMPLE 97 Preparation of 2-(6-carboxyheptyl)-2-cyclopentenone methoxime

Saponification of 2-(6,6-dicarbethoxyheptyl)-2-cyclopentenone methoxime (Example 96) with potassium hydroxide by the method of Example 20 is productive of 2-(6,6-dicarboxyheptyl)-2-cyclopentenone methoxime, decarboxylation of which in the manner of Example 63 provides the subject compound

EXAMPLE 98 Preparation of 2-(6-carboxyheptyl)-2-cyclopentenone

Methoxime cleavage of 2-(6-carboxyheptyl)-2-cyclopentenone methoxime (Example 97 ) in the manner of Example 22 provides the subject ketone.

EXAMPLE 99 Preparation of 2-(6-carbethoxyheptyl)-2-cyclopentenone

Esterification with ethanol of the acid chloride derived from 2-(6-carboxyheptyl)-2-cyclopentenone in the manner of Example 31 is productive of the subject compound.

EXAMPLE 100 Preparation of ethyl (methyl) 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate

To a stirred suspension of 51 g. of sodium hydride (57% in mineral oil) in 675 ml. of dimethylformamide is added 200 g. of 2-cyclohexanone carboxylate (60% ethyl -40% methyl esters) over a 1-5 hr. period with external cooling to maintain the temperature at 20°-25° C. The reaction mixture is stirred at ambient temperature for 15 minutes and heated to 50° C. over 15 minutes. To the stirred mixture is added 300 g. of ethyl 7-bromoheptanoate during a 10 minute period. The reaction mixture is stirred at 50°-60° C. for 4 hours, cooled, and poured into water. The product is obtained by ether extraction. The extract is washed successively with water and saturated sodium chloride, dried and evaporated to give a liquid which is purified by distillation, IR 1735 cm⁻¹ (ester carbonyls) and 1710 cm⁻¹ (ketone carbonyl). cl EXAMPLE 101

Preparation of 7 -(cyclohexan-1-on-2-yl)heptanoic acid

A stirred mixture of 380 g of mixed methyl and ethyl esters of 7-(2-carbethoxycyclohexan-1-on-2-yl)heptanoate (Example 10), 202 ml of concentrated sulfuric acid, 970 ml of glacial acetic acid, and 970 ml of water is refluxed for 22.5 hours. The cooled reaction mixture is treated with 380 g. of sodium carbonate and 2 liters of water and is extracted with ether. Acidic material is partition from the ether extract with 1.0M sodium carbonate. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated to give an oil.

EXAMPLE 102 Preparation of ethyl 7-(cyclohexan-1-on-2-yl)heptanoate

A solution of 232 g of 7-(cyclohexan-1-on-2-yl)heptanoic acid in 2500 ml. of ethanol is refluxed for 4.5 hours with 3.8 g of p-toluenesulfonic acid monohydrate. The solution is diluted with 200 ml. of benzene, and boiling is continued for 2 hours as 200 ml. of distillate is removed. The volume of the solution is concentrated to 500 ml. After dilution with 500 ml. of ether the solution is extracted with a solution prepared from 50 ml. of saturated sodium bicarbonate, 50 ml. of saturated sodium chloride, and 100 ml. of water. The extract is washed with saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm⁻¹ (ester carbonyl) and 1715 cm⁻¹ (ketone carbonyl).

EXAMPLE 103 Preparation of 2-carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclohexan-1-one

The subject compound is prepared in the manner described in Example 10 by treatment of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with sodium hydride and ethyl 4-iodobutyrate.

EXAMPLE 104 Preparation of 2-(3-carbethoxypropyl)cyclohexan-1-one

This compound is prepared from 2carbalkoxy(methyl/ethyl)-2-(3-carbethoxypropyl)cyclohexan-1-one (Example 13) by decarbalkoxylation according to the procedure described in Example 11 followed by esterification by the procedure of Example 12.

EXAMPLE 105 Preparation of 2-(5-carbethoxypentyl)cyclohexan-1-one

This compound is prepared by alkylation of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with ethyl 6-bromohexanoate according to the procedure of Example 10, followed by decarbalkoxylation according to the procedure of Example 11 and finally esterification by the procedure of Example 12.

EXAMPLE 106 Preparation of 2-(7-carbethoxyheptyl)cyclohexan-1-one

Alkylation of 2-cyclohexanone carboxylate (mixed methyl and ethyl esters) with ethyl 8-bromoctanoate in accordance with the procedure of Example 10, followed by decarbalkoxylation by the procedure of Example 11 and then esterification by the procedure of Example 12 is productive of the subject compound.

EXAMPLE 107 Preparation of ethyl 7-(1-acetoxycyclohex-1-en-2-yl)heptanoate

A stirred solution of 28.0 g of ethyl 7-(cyclohexan-1-on-2-yl)heptanoate (Example 12), 170 mg. of p-toluenesulfonic acid monohydrate, and 25.6 g. of acetic anhydride is heated for 5 hours while allowing 8.0 g. of distillate to distill. The cooled solution is poured into a stirred, ice-cold mixture of 500 ml. of saturated sodium bicarbonate and 250 ml. of hexane. After one hour the hexane phase is separated, dried, and evaporated. The crude product is distilled to give a liquid, IR 1760 cm⁻¹ (vinyl ester carbonyl) and 1740 cm⁻¹ (ethyl ester carbonyl).

EXAMPLE 108 Preparation of 1-acetoxy-2-(3-carbethoxypropyl)cyclohex-1-ene

Treatment of 2-(3-carbethoxypropyl)cyclohexan-1-one (Example 14) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.

EXAMPLE 109 Preparation of 1-acetoxy-2-(5-carbethoxypentyl)cyclohex-1-ene

Treatment of 2-(5-carbethoxypentyl)cyclohexan-1-one (Example 15 ) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.

EXAMPLE 110 Preparation of 1acetoxy-2-(7-carbethoxyheptyl)cyclohex-1-ene

Treatment of 2-(7-carbethoxyheptyl)cyclohexan-1-one (Example 16) with acetic anhydride by the procedure of Example 24 is productive of the subject compound.

EXAMPLE 111 Preparation of ethyl 7-(cyclohex-2-en-1-one-2-yl) heptanoate

To a stirred solution of ethyl 7-(1-acetoxycyclohex-1en--2-yl)heptanoate (Example 24) in 750 ml. of acetic acid and 125 ml. of pyridine at 10° C. is added a solution of 13.8 g. of bromine in 200 ml. of acetic acid over 20 minutes. The resulting solution is allowed to stand at ambient temperature for 45 minutes and is then decolorized with sodium sulfite. The solution is poured into 800 ml. of half-saturated sodium chloride and extracted with 1:1 hexane-ether. The extract is washed successively with water and saturated sodium chloride, dried over sodium carbonate, and evaporated to give 32 g. of the crude bromoketone. To a stirred suspension of 14.2 g. of lithium bromide and 16.6 g. of lithium carbonate in 250 ml. of anhydrous dimethylformamide at 80° C. is added the above bromoketone. The stirred mixture is heated to boiling over 20 minutes and refluxed for 15 minutes. The cooled mixture is poured into 1000 ml. of water, acidified with dilute hydrochloric acid, and extracted with ether. The extract is washed successively with water and saturated sodium chloride, dried, and evaporated. The product is purified by distillation to give a liquid, IR 1740 cm⁻¹ (ester carbonyl), 1685 cm⁻¹ (ketone carbonyl), and 1650 cm⁻¹ (olefin); NMR (CCl₄) 6.63 (multiplet, vinyl proton).

EXAMPLE 112 Preparation of 2-(3-carbethoxypropyl)cyclohex-2-en-1-one

In accordance with the procedure of Example 40, bromination of 1-acetoxy-2-(3-carbethoxypropyl)cyclohex-1ene (Example 25) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 113 Preparation of 2-(5-carbethoxypentyl)cyclohex-2-en-1-one

By the procedure of Example 40, bromination of 1-acetoxy-2-(5-carbethoxypentyl)cyclohex-1-ene (Example 26) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 114 Preparation of 2-(7-carbethoxyheptyl)cyclohex-1-en-2-one

By the procedure of Example 40, bromination of 1-acetoxy-2-(7-carbethoxyheptyl)cyclohex-1-ene (Example 27) followed by treatment with lithium bromide and lithium carbonate is productive of the subject compound.

EXAMPLE 115 Preparation of 2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene

In the manner described in Example 34, treatment of 2-(4-hydroxybutyl)-1-methoximino-2-cyclopentene with p-toluene sulfonyl chloride in pyridine gives the subject product as a light yellow oil; IR (film): 1600, 1190, 1050, 885 cm⁻¹.

EXAMPLE 116 Preparation of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene

To a stirred mixture of 1.465 g. (0.0348 mole) of sodium hydride (57.2% in mineral oil) in 50 ml of dimethoxethane, under nitrogen, is added slowly 4.8 g. (0.0347 mole) of ethyl-2-mercaptoacetate. The reaction mixture is stirred at room temperature for one hour and then a solution of 7.8 g. (0.0231 mole) 2-(4-p-toluenesulfonyloxybutyl)-1-methoximino-2-cyclopentene in 30 ml. of dimethoxyethane is added dropwise and stirred at room temperature for 18 hours. The slution is heated at reflux for one hour, cooled and poured into cold dilute hydrochloric acid and then extracted with ether. The combined ether extracts are washed with saline, dried over magnesium sulfate and evaporated to give 7.6 g of subject product as a yellow oil.

EXAMPLE 117 Preparation of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 38, treatment of 2-(6-carbethoxy-5-thiahexyl)-1-methoximino-2-cyclopentene with acetone and 2N hydrochloric acid at reflux gives the subject product as a yellow oil.

EXAMPLE 118 Preparation of 2-(6-carbethoxy-5-thiahexyl)-2-cyclopentenone

In the manner described in Example 39, treatment of 2-(6-carboxy-5-thiahexyl)-2-cyclopentenone with p-toluenesulfonic acid in ethanol gives the subject ester as a yellow oil.

EXAMPLE 119 Preparation of 3-triphenylmethoxy-1-octyne

A mixture of 1.26 g (10.0 mmoles) of 1-octyn-3-ol, 4.85 g (15.0 mmoles) of triphenylmethyl bromide, and b 50 ml. of dry pyridine is heated at 95° C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrystallization from petroleum ether to give white crystals, m.p. 65°-66.5°, νmax. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm⁻¹ (triphenylmethoxy group).

EXAMPLE 120 Preparation of ethyl 9-oxo-15-triphenylmethoxy-13-trans-8ξ-prostenoate

A stirred solution of 7.37 g. (20.0 mmoles ) of 3-triphenylmethoxy-1-octyne (Example 119) in 10 ml. of benzene is treated with 16.7 mg. of 1.2 M. diisobutylaluminum hydride in hexane, and the resulting solution is heated at 50° C. for 2 hours. The solution is cooled to 0° C. and treated with 10.5 ml. of 1.7 M methyl lithium in ether. After stirring for a 20 minute period at ambient temperature, the alanate solution is cooled to 0° C. and treated with a solution of 3.98 g. (16.7 mmoles) of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 13) in 5 ml. of ether. The resulting solution is stirred at ambient temperature for 22.5 hours, diluted with ether, and poured into a stirred mixture 2N acetic acid and ice. After stirring until methane evolution ceases, the organic phase is separated and washed successively with water and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. The crude product in the residue is purified by chromatography on silica gel to give an oil, νmax. 1735 (carbonyl groups), 967 (trans vinyl group), and 705 cm⁻¹ (triphenylmethoxy group).

EXAMPLE 121 Preparation of ethyl 15-hydroxy-9-oxo-13-trans-prostenoate

A 0.05M solution of ethyl 9-oxo-15-triphenylmethoxy-13-trans-8ξ-prostenoate (Example 120) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45° C. for 3.5 hours. The solvents are evaporated at reduced pressure, and the residue is dissolved in ether. The solution is washed successively with water, 0.5N sodium bicarbonate solution, and saturated sodium chloride solution; dried over magnesium sulfate; and concentrated. Column chromatograhy of the crude product on silica gel gives two epimeric substances which are purified separately by thin layer chromatography to give oils differing only in chromatographic behavior, νmax. 3470 (hydroxyl group), 1735 (carbonyl groups), and 967 cm⁻¹ (trans vinyl group).

EXAMPLE 122 Preparation of 15-hydroxy-9-oxo-13-trans-prostenoic acid

A solution of 2 g. of ethyl 15-hydroxy-9-oxo-13,14-trans-prostenoate (Example 121) (mixture of racemates) in 32 ml. of methanol-water (1:1) containing 850 mg. of potassium hydroxide is stirred at ambient temperature for 18 hours. After acidification with 10% hydrochloric acid, the solution is extracted with ether several times. The combined ether extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.69 g. (92%) of an oil which partially crystallizes. Recrystallized from ether-hexane gives white crystals, m.p. 79°-81° C.; nmr δ6.36 (s, hydroxyl and carboxyl groups) 5.61 (t, olefinic protons), 4.12 (s, C₁₅ -H) and 0.90 (s, terminal methyl).

EXAMPLE 123 Preparation of tetrahydropyran-2-yl 9-oxo-11-tetrahydropyranyloxy-15-triphenylmethoxy-13-trans-8ξ-prostenoate

In the manner described in Example 120, 13.6 g. (37 mmoles) of 3-triphenylmethoxy-1-octyne (Example 119) contained in 18.5 ml. of benzene is converted to an alanate reagent by treatment with 31 ml. of 1-2M diisobutylaluminum hydride in hexane and 21 ml. of 1.7M methyl lithium in ether. To the stirred, ice-cold reagent is added a solution of 10.97 g. (24.6 mmoles) of 2-(6-tetrahydropyranylcarboxyhexyl)-4-tetrahydropyranyloxycyclopent-2-en-1-one (Example 95) in 10 ml. of ether during 10 minutes. The resulting solution is stirred at ambient temperature for 20 hours, diluted with ether, and poured into a stirred mixture of 2N hydrochloric acid and ice. The organic phase is separated and washed successively with water and saturated sodium chloride solution. The extract is dried over magnesium sulfate, and the solvents are evaporated at reduced pressure to give the crude product as an oil, νmax. 1735 (carbonyl groups), 1030 (tetrahydropyranyloxy groups), 970 (trans vinyl group), and 705 cm⁻¹ (triphenylmethoxy group).

EXAMPLE 124 Preparation of 11,15-dihydroxy-9-oxo-13-trans-prostenoic acids

A 0.05M solution of crude tetrahydropyran-2-yl 9-oxo-11-tetrahydropyranyloxy-15-triphenylmethoxy-13-trans-prostenoate (Example 123) in glacial acetic acid-tetrahydrofuran-water (4:2:1) is heated at 45° C. for 3.5 hours. The solution is diluted with water and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate. The solvents are removed at reduced pressure. Column chromatography of the residue on acid-washed silica gel gives the title compounds as a pair of epimeric substances which are purified separately by partition chromatography.

The fast-running epimer (15-epi-d,l-prostaglandin E₁) is obtained as an oil, νmax. 1735 (ketone carbonyl group), 1710 (acid carbonyl group), and 967 cm⁻¹ (trans vinyl group); NMR (acetone-d₆) 5.68 (multiplet, vinyl hydrogens) and 4.11 δ(multiplet, carbinolic hydrogens).

The slow-running epimer (d,l-prostaglandin E₁) is recrystallized from ethyl acetate-petroleum ether to give white crystals, m.p. 100°-105° C., νmax. (KBr) 1725 (ketone carbonyl group), 1700 (acid carbonyl group), and 970 cm⁻ (trans vinyl group); NMR (acetone-d₆) 5.67 (multiplet, vinyl hydrogens) and 4.12 (multiplet, carbinolic hydrogens).

EXAMPLES 125 to 139

In accordance with the method described in Example 119, the various 3-hydroxy-1-alkynes listed in the table below are converted to the corresponding 3-triphenylmethoxy-1-alkynes by treatment with triphenylmethyl bromide.

                  TABLE                                                            ______________________________________                                         125  1-heptyn-3-ol    3-triphenylmethoxyheptyne-1                              126  1-hexyne-3-ol    3-triphenylmethoxy-hexyne-1                              127  1-pentyn-3-ol    3-triphenylmethoxy-pentyne-1                             128  1-nonyne-3-ol.sup.a                                                                             3-triphenylmethoxy-nonyne-1                              129  1-decyne-3-ol.sup.b                                                                             3-triphenylmethoxy-decyne-1                              130  4-ethyl-1-octyne-3-ol                                                                           3-triphenylmethoxy-4-ethyl-                                                    octyne-1                                                 131  4-ethyl-1-hexyne-3-ol                                                                           3-triphenylmethoxy-4-ethyl-                                                    hexyne-1                                                 132  4-methyl-1-heptyne-3-ol                                                                         3-triphenylmethoxy-4-methyl-                                                   heptyne-1                                                133  4-methyl-1-pentyne-3-ol                                                                         3-triphenylmethoxy-4-methyl-                                                   pentyne-1                                                134  7-methyl-6-en-1-octyne-                                                                         3-triphenylmethoxy-7-methyl-                                  3-ol.sup.c       6-en-octyne-1                                            135  6,7-dimethyl-6-en-1-                                                                            3-triphenylmethoxy-6,7-                                       octyne-3-ol.sup.c                                                                               dimethyl-6-en-octyne-1                                   136  7-isobutyl-6-en-1-                                                                              3-ytriphenylmethoxy-7-isobutyl-                               octyne-3-ol.sup.c                                                                               6-en-octyne-1                                            137  5-en-1-hexyne-3-ol.sup.d                                                                        3-triphenylmethoxy-5-en-                                                       hexyne-1                                                 138  5,9-dimethyl-9-en-1-                                                                            3-triphenylmethoxy-5,9-                                       decyne-3-ol.sup.e                                                                               dimethyl-9-en-decyne-1                                   139  cis-5-en-1-octyne-3-                                                                            3-triphenylmethoxy-cis-5-en-                                  ol.sup.f         octyne-1                                                 ______________________________________                                          References:                                                                    .sup.a M. Bertrand, Bull. Soc. Chim. France, 461 (1956).                       .sup.b F. Bohlmann and D. Ratz, Chem. Ber., 90, 2265 (1957).                   .sup.c U.S. Pat. 3,452,105 (June 24, 1969); Chem. Abs., 71, 60678 (1969).      .sup.d A. Viola and J. H. MacMillan, Jour. Amer. Chem. Soc., 92, 2404          (1970).                                                                        .sup.e Sequin, Bull. Soc. Chim. France, 12, 948 (1945).                        .sup.f J. Fried et al., Jour. Amer. Chem. Soc., 94, 4342 (1972).         

EXAMPLES 140-256

Treatment of the cycloalkenone designated in the table below with the alanate [lithium diisobutyl-methyl(3-triphenylmethoxy-1-trans-alkenyl)-alanate] prepared by treatment of the listed 3-triphenylmethoxy-1-alkyne with diisobutyl aluminum hydride followed with methyl lithium, all by the procedure described in Example 120, is productive 9-oxo-15-triphenylmethoxy-13-trans-8-ξ-prostenoates of the table.

                                      Table 3                                      __________________________________________________________________________          Starting                                                                               Starting 3-triphenyl-                                                                    Product                                                      Cycloalkenone                                                                          methoxy-1-alkyne of                                                                      Alkyl 9-oxo-15-triphenylmethoxy-13-trans-               Example                                                                             of Example                                                                             Example   8ξ-prostenoate                                       __________________________________________________________________________     140  14      119       ethyl 9-oxo-15-triphenylmethoxy-5,6,7-tri-                                     nor-13-trans-8ξ-prostenoate                          141  23      119       ethyl 9-oxo-15-triphenylmethoxy-7a,7b-bis-                                     homo-13-trans-8ξ-prostenoate                         142  31      119       ethyl 9-oxo-15-triphenylmethoxy-2-ethyl-13-                                    trans-8ξ-prostenoate                                 143  41      119       ethyl 9-oxo-15-triphenylmethoxy-3,3-dimethyl-                                  13-trans-8ξ-prostenoate                              144  46      119       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-13-                                      trans-8ξ-prostenoate                                 145  53      119       ethyl 9-oxo-15-triphenylmethoxy-7-nor-13-                                      trans-8ξ-prostenoate                                 146  70      119       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-13-                                   trans-8ξ-prostenoate                                 147  74      119       ethyl 9-oxo-15-triphenylmethoxy-7a-homo-13-                                    13-trans-8ξ-prostenoate                              148  79      119       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-13-                                   trans-8ξ-prostenoate                                 149  99      119       ethyl 9-oxo-15-triphenylmethoxy-2-methyl-13-                                   trans-8ξ-prostenaoate                                150  111     119       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-13-                                   trans-8ξ-prostenoate                                 151  112     119       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-5,-                                   6,7-trinor-13-trans-8ξ-prostenoate                   152  113     119       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-7-                                    nor-13-trans-8ξ-prostenoate                          153  114     119       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bis-                                    homo-13-trans-8ξ-prostenoate                         154  118     119       ethyl 9-oxo-15-triphenylmethoxy-3-thia-13-                                     13-trans-8ξ-prostenoate                              155  81      119       butyl 9-oxo-15-triphenylmethoxy-13-trans-8ξ-                                prostenoate                                             156  82      119       isopropyl 9-oxo-15-triphenylmethoxy-13-trans-                                  8ξ-prostenoate                                       157  83      119       methyl 9-oxo-15-triphenylmethoxy-13-trans-8ξ-                               prostenoate                                             158  84      119       n-deycl 9-oxo-15-triphenylmethoxy-13-trans-                                    8ξ-prostenoate                                       159  900     119       methyl 9-oxo-15-triphenylmethoxy-5-cis,13-                                     trans-8ξ-prostadienoate                              160  13      125       ethyl 9-oxo-15-triphenylmethoxy-20-nor-13-                                     trans-8ξ-prostenoate                                 161  13      128       ethyl 9-oxo-15-triphenylmethoxy-20-methyl-                                     13-trans-8ξ-prostenoate                              162  13      130       ethyl 9-oxo-15-triphenylmethoxy-16-ethyl-13-                                   trans-8ξ-prostenoate                                 163  13      132       ethyl 9-oxo-15-triphenylmethoxy-16-methyl-20-                                  nor-13-trans-8ξ-prostenoate                          164  13      134       ethyl 9-oxo-15-triphenylmethoxy-19-methyl-13-                                  trans,18-8ξ-prostadienoate                           165  13      135       ethyl 9-oxo-15-triphenylmethoxy-18,19-di-                                      methyl-13-trans,18-8ξ-prostadienoate                 166  13      139       ethyl 9-oxo-15-triphenylmethoxy-8ξ-13-trans,                                17-cis-prostadienoate                                   167  14      139       ethyl 9-oxo-15-triphenylmethoxy-5,6,7-trinor-                                  8ξ-13-trans,17-cis-prostadienoate                    168  15      139       ethyl 9-oxo-15-triphenylmethoxy-6,7-dinor-8ξ-                               13-trans,17-cis-prostadienoate                          169  23      139       ethyl 9-oxo-15-triphenylmethoxy-7a,7b-bishomo-                                 8ξ-13-trans,17-cis-prostadienoate                    170  31      139       ethyl 9-oxo-15-triphenylmethoxy-2-ethyl-8ξ-13-                              trans,17-cis-prostadienoate                             171  41      139       ethyl 9-oxo-15-triphenylmethoxy-3,3-dimethyl-                                  8ξ-13-trans,17-cis-prostadienoate                    172  46      139       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-8ξ-13-                                trans,17-cis-prostadienoate                             173  53      139       ethyl 9-oxo-15-triphenylmethoxy-7-nor-8ξ-13-                                trans,17-cis-prostadienoate                             174  70      139       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-8ξ-13-                             1                                                                              trans,17-cis-prostadienoate                             175  74      139       ethyl 9-oxo-15-triphenylmethoxy-7a-homo-8ξ-13-                              trans,17-cis-prostadienoate                             176  79      139       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-8ξ-13-                             5                                                                              trans,17-cis-prostadienoate                             177  99      139       ethyl 9-oxo-15-triphenylmethoxy-2-methyl-8ξ-13-                             .                                                                              trans,17-cis-prostadienoate                             178  111     139       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-8ξ-13-                             8                                                                              trans,17-cis-prostadienoate                             179  112     139       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-5,6,7-                                trinor-13-trans,17-cis-prostadienoate                   180  113     139       ethyl 9-oxo-15-tripenylmethoxy-10a-homo-7-nor-                                 8ξ-13-trans,17-cis-prostadienoate                    181  114     139       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bishomo-                                8ξ-13-trans,17-cis-prostadienoate                    182  118     139       ethyl 9-oxo-15-triphenylmethoxy-3-thia-8ξ-13-                               trans,17-cis-prostadienoate                             183  81      139       butyl 9-oxo-15-triphenylmethoxy-8ξ-13-trans,17-                             4                                                                              cis-prostadienoate                                      184  82      139       isopropyl 9-oxo-15-triphenylmethoxy-8ξ                                      -13-trans,-                                                                    cis-prostadienoate                                      185  83      139       methyl 9-oxo-15-tripenylmethoxy-8ξ-13-trans,                                17-cis-prostadienoate                                   186  84      139       n-decyl 9-oxo-15-triphenylmethoxy-8ξ-13-trans,17                            -                                                                              cis-prostadienoate                                      187  14      136       ethyl 9-oxo-15-triphenylmethoxy-5,6,7-trinor-19-                               isobutyl-8ξ-13-trans,18-prostadienoate               188  14      137       ethyl 9-oxo-15-triphenylmethoxy-5,6,7,19,20-penta                              nor-8ξ-13-trans-17,prostadienoate                    189  13      137       ethyl 9-oxo-15-triphenylmethoxy-19,20-dinor-8ξ-1                            3-                                                                             trans,18-prostadienoate                                 190  13      138       ethyl 9-oxo-15-triphenylmethoxy-17-methyl-20-iso-                              propenyl-8ξ-trans-prostenoate                        191  15      131       ethyl 9-oxo-15-triphenylmethoxy-16-ethyl-6,7,19,                               20-tetranor-8ξ-13-trans-prostenoate                  192  15      135       ethyl 9-oxo-15-triphenylmethoxy-18,19-dimethyl-6,                              7-dinor-8ξ-13-trans,18-prostadienate                 193  23      130       ethyl 9-oxo-15-triphenylmethoxy-16-ethyl-7a,7b-                                bishomo-8ξ-13-trans-prostenoate                      194  23      134       ethyl 9-oxo-15-triphenylmethoxy-19-methyl-7a,7b-                               bishomo-8ξ-13-trans,18-prostadienoate                195  31      126       ethyl 9-oxo-15-triphenylmethoxy-2-ethyl-19,20-                                 dinor-8ξ-13-trans-prostenoate                        196  31      129       ethyl 9-oxo-15-triphenylmethoxy-2,20-diethyl-                                  8ξ-13-trans-prostenoate                              197  31      132       ethyl 9-oxo-15-triphenylmethoxy-2-ethyl-16-                                    methyl-8ξ-20-nor-13-trans-prostenoate                198  31      135       ethyl 9-oxo-15-triphenylmethoxy-2-ethyl-18,                                    19-dimethyl-8ξ-13-trans,18-prostadienoate            199  41      127       ethyl 9-oxo-15-triphenylmethoxy-3,3-dimethyl-                                  18,19,20-trinor-8ξ-13-trans-prostenoate              200  41      128       ethyl 9-oxo-15-triphenylmethoxy-3,3,20-tri-                                    methyl-8ξ-13-trans-prostenoate                       201  41      132       ethyl 9-oxo-15-triphenylmethoxy-3,3,16-tri-                                    methyl-20-nor-8ξ-13-trans-prostenoate                202  41      136       ethyl 9-oxo-15-triphenylmethoxy-3,3-dimethyl-                                  19-isobutyl-8ξ-13-trans,18-prostadienoate            203  41      137       ethyl 9-oxo-15-triphenylmethoxy-3,3-dimethyl-                                  19,20-dinor-8ξ-13-trans,17-prostadienoate            204  46      125       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-20-nor-                                  8ξ-13-trans-prostenoate                              205  46      128       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-20-                                      methyl-8ξ-13-trans-prostenoate                       206  46      130       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-16-                                      ethyl-8ξ-13-trans-prostenoate                        207  46      132       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-16-                                      methyl-20-nor-8ξ-13-trans-prostenoate                208  46      137       ethyl 9-oxo-15-triphenylmethoxy-3-oxa-19,20-                                   dinor-8ξ-13-trans,17-prostadienoate                  209  53      137       ethyl 9-oxo-15-triphenylmethoxy-7,19,20-tri                                    nor-8ξ-13-trans,17-prostadienoate                    210  53      135       ethyl 9-oxo-15-triphenylmethoxy-7-nor-18,19-                                   dimethyl-8ξ-13-trans,18-prostadienoate               211  53      133       ethyl 9-oxo-15-triphenylmethoxy-7,18,19,20-                                    tetranor-16-methyl-8ξ-13-trans-prostenoate           212  70      125       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-20-                                   nor-8ξ-13-trans-prostenoate                          213  70      129       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-20-                                   ethyl-8ξ-13-trans-prostenoate                        214  70      131       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-16-                                   ethyl-19,20-dinor-8ξ-13-trans-prostenoate                                   -215 70 132 ethyl 9-oxo-15-triphenylmethoxy-2-fluor                            o-16-                                                                          methyl-20-nor-8ξ-13-trans-prostenoate                216  70      134       ethyl 9-oxo-15-triphenylmethoxy-2-fluoro-19-                                   methyl-8ξ-13-trans,18-prostadienoate                 217  74      135       ethyl 9-oxo-15-triphenylmethoxy-7a-homo-18,19-                                 dimethyl-8ξ-13-trans,18-prostadienoate               218  74      137       ethyl 9-oxo-15-triphenylmethoxy-7a-homo-19,20-                                 dinor-8ξ-13-trans,17-prostadienoate                  219  79      125       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-20-                                   nor-8ξ-13-trans-prostenoate                          220  79      129       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-20-                                   ethyl-8ξ-13-trans-prostenoate                        221  79      130       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-16-                                   ethyl-8ξ-13-trans-prostenoate                        222  79      133       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-16-                                   methyl-18,19,20-trinor-8ξ-trans-prostenoate          223  79      135       ethyl 9-oxo-15-triphenylmethoxy-2-phenyl-18,-                                  19,-dimethyl-8ξ-13-trans,18-prostadienoate           224  99      125       ethyl 9-oxo-15-triphenylmethoxy-2-methyl-20-                                   nor-8ξ-13-trans-prostenoate                          225  99      128       ethyl 9-oxo-15-triphenylmethoxy-2,20-dimethyl-                                 8ξ-13-trans-prostenoate                              226  99      131       ethyl 9-oxo-15-triphenylmethoxy-2-methyl-16-                                   ethyl-19,20-dinor-8ξ-13-trans-prostenoate            227  99      134       ethyl 9-oxo-15-triphenylmethoxy-2,19-dimethyl-                                 8ξ-13-trans,18-prostadienoate                        228  99      137       ethyl 9-oxo-15-triphenylmethoxy-2-methyl-19,                                   20-dinor-8ξ-13-trans,17-prostadienoate               229  111     125       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-20-                                   nor-8ξ-13-trans-prostenoate                          230  111     128       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-20-                                   methyl-8ξ-13-trans-prostenoate                       231  111     130       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-16-                                   ethyl-8ξ-13-trans-prostenoate                        232  111     135       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-18,                                   19-dimethyl-8ξ-13-trans,18-prostadienoate            233  111     137       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-19,                                   20-dinor-8ξ  -13-trans,17-prostadienoate             234  112     129       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-5,6,                                  7-trinor-20-ethyl-8ξ-13-trans-prostenoate            235  112     132       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-5,6,                                  7,20-tetranor-16-methyl-8ξ-13-trans-prost-                                  enoate                                                  236  112     136       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-5,6,7-                                trinor-19-isobutyl-8ξ-13-trans,18-prostadienoate                            O                                                       237  113     128       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-20-                                   methyl-8ξ-13-trans-prostenoate                       238  113     134       ethyl 9-oxo-15-triphenylmethoxy-10a-homo-19-                                   methyl-8ξ-13-trans,18-prostadienoate                 239  114     125       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bis-                                    homo-20-nor-8ξ-13-trans-prostenoate                  240  114     129       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bis-                                    homo-20-ethyl-8ξ-13-trans-prostenoate                241  114     132       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bis-                                    homo-16-methyl-20-nor-8ξ-13-trans-prostenoate        242  114     134       ethyl 9-oxo-15-triphenylmethoxy-7a,10a-bis-                                    homo-19-methyl-8ξ-13-trans,18-prostadienoate         243  118     125       ethyl 9-oxo-15-triphenylmethoxy-3-thia-20-nor-                                 8ξ-13-trans-prostenoate                              244  118     128       ethyl 9-oxo-15-triphenylmethoxy-3-thia-20-methyl-                              8ξ-13-trans-prostenoate                              245  118     130       ethyl 9-oxo-15-triphenylmethoxy-3-thia-16-ethyl-                               8ξ-13-trans-prostenoate                              246  118     133       ethyl 9-oxo-15-triphenylmethoxy-3-thia-16-                                     methyl-18,19,20-trinor-8ξ-13-trans-prostenoate       247  118     134       ethyl 9-oxo-15-triphenylmethoxy-3-thia-19-methyl-                              8ξ-13-trans,18-prostadienoate                        248  118     137       ethyl 9-oxo-15-triphenylmethoxy-3-thia-19,20-                                  dinor-8ξ-13-trans,17-prostadienoate                  249  900     125       methyl 9-oxo-15-triphenylmethoxy-20-nor-8ξ-5-                               cis,13-trans-prostadienoate                             250  900     128       methyl 9-oxo-15-triphenylmethoxy-20-methyl-8ξ-5-                            N                                                                              cis,13-trans-prostadienoate                             251  900     130       methyl 9-oxo-15-triphenylmethoxy-16-ethyl-8ξ-5-                             O                                                                              cis,13-trans-prostadienoate                             252  900     132       methyl 9-oxo-15-triphenylmethoxy-16-methyl-20-                                 nor-8ξ-cis,13-trans-prostadienoate                   253  900     134       methyl 9-oxo-15-triphenylmethoxy-19-methyl-8ξ-5-                            cis,13-trans,18-prostadienoate                          254  900     135       methyl 9-oxo-15-triphenylmethoxy-18,19-dimethyl-                               8ξ-5-cis,13-trans,18-prostatrienoate                 255  900     137       methyl 9-oxo-15-triphenylmethoxy-19,20-dinor-8ξ-                            N                                                                              5-cis,13-trans,17-prostatrienoate                       256  900     139       methyl 9-oxo-15-triphenylmethoxy-8ξ-5-cis,13-                               trans,17-cis-prostatrienoate                            __________________________________________________________________________

EXAMPLE 257 Preparation of ethyl 9α/β,15-dihydroxy-13-trans-prostenoate

A solution containing 3 g. of ethyl 9-oxo-15-hydroxy-13-trans-prostenoate (Example 121) in 120 ml. of absolute alcohol containing 115 mg. of sodium borohydride is stirred at ambient temperature for 18 hours. The solution is poured into 300 ml. of saturated sodium chloride solution and the oily precipitate is extracted with ether. The ether is washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give subject product as an oil; λ max. 2195, 5178, 8.45 μ; the product is a mixture of 9α- and 9β-hydroxy derivatives.

EXAMPLES 258-374

Treatment of the designated 9-oxo-15-triphenylmethoxy derivatives listed in the table below, with glacial acetic acid-tetrahydropyran-water (4:2:1) in the manner described in Example 121 is productive of the corresponding 15-hydroxy derivatives of the table. This acid treatment also ensures a trans-relationship between the two side-chains attached to C₈ and C₁₂.

                  TABLE 4                                                          ______________________________________                                                Starting 15-tri-                                                               phenylmethoxy Product Alkyl 9-oxo-                                      Ex-    derivative of 15-hydroxy-13-trans-                                      ample  Example       prostenoates                                              ______________________________________                                         258    140           Ethyl 9-oxo-15-hydroxy-                                                        5,6,7-trinor-13-trans-                                                         prostenoate                                               259    141           Ethyl 9-oxo-15-hydroxy-                                                        7a,7b-bishomo-13-                                                              trans-prostenoate                                         260    142           Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-13-trans-                                                              prostenoate                                               261    143           Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-13-trans-                                                         prostenoate                                               262    144           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-13-trans-                                                                prostenoate                                               263    145           Ethyl 9-oxo-15-hydroxy-                                                        7-nor-13-trans-                                                                prostenoate                                               264    146           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-13-trans-                                                             prostenoate                                               265    147           Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-13-trans-                                                              prostenoate                                               266    148           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-13-trans-                                                             prostenoate                                               267    149           Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-13-trans-                                                             prostenoate                                               268    150           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-13-trans-                                                             prostenoate                                               269    151           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-5,6,7-trinor-                                                         13-trans-prostenoate                                      270    152           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-7-nor-13-                                                             trans-prostenoate                                         271    153           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-13-                                                             trans-prostenoate                                         272    154           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-13-trans-                                                               prostenoate                                               273    155           Butyl 9-oxo-15-hydroxy-                                                        13-trans-prostenoate                                      274    156           Isopropyl 9-oxo-15-                                                            hydroxy-13-trans-                                                              prostenoate                                               275    157           Methyl 9-oxo-15-hydroxy-                                                       13-trans-prostenoate                                      276    158           n-decyl 9-oxo-15-                                                              hydroxy-13-trans-                                                              prostenoate                                               277    159           Methyl 9-oxo-15-                                                               hydroxy-5-cis,-13-                                                             trans-prostadienoate                                      278    160           Ethyl 9-oxo-15-hydroxy-                                                        20-nor-13-trans-                                                               prostenoate                                               279    161           Ethyl 9-oxo-15-hydroxy-                                                        20-methyl-13-trans-                                                            prostenoate                                               280    162           Ethyl 9-oxo-15-hydroxy-                                                        16-ethyl-13-trans-                                                             prostenoate                                               281    163           Ethyl 9-oxo-15-hydroxy-                                                        16-methyl-20-nor-13-                                                           trans-prostenoate                                         282    164           Ethyl 9-oxo-15-hydroxy-                                                        19-methyl-13-trans,18-                                                         prostadienoate                                            283    165           Ethyl 9-oxo-15-hydroxy-                                                        18,19-dimethyl-13-                                                             trans,18-prostadienoate                                   284    166           Ethyl 9-oxo-15-hydroxy-                                                        13-trans,17-cis-                                                               prostadienoate                                            285    167           Ethyl 9-oxo-15-hydroxy-                                                        5,6,7-trinor-13-trans,                                                         17-cis-prostadienoate                                     286    168           Ethyl 9-oxo-15-hydroxy-                                                        6,7-dinor-13-trans-                                                            17-cis-prostadienoate                                     287    169           Ethyl 9-oxo-15-hydroxy-                                                        7a,7b-bishomo-13-                                                              trans,17-cis-prosta-                                                           dienoate                                                  288    170           Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-13-trans,17-                                                           cis-prostadienoate                                        289    171           Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-13-trans,                                                         17-cis-prostadienoate                                     290    172           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-13-trans,17-cis-                                                         prostadienoate                                            291    173           Ethyl 9-oxo-15-hydroxy-                                                        7-nor-13-trans,17-cis-                                                         prostadienoate                                            292    174           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-13-trans,17-                                                          cis-prostadienoate                                        293    175           Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-13-trans,17-                                                           cis-prostadienoate                                        294    176           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-13-trans,17-                                                          cis-prostadienoate                                        295    177           Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-13-trans,17-                                                          cis-prostadienoate                                        296    178           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-13-trans,17-                                                          cis-prostadienoate                                        297    179           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-5,6,7-trinor-                                                         13-trans,17-cis-prosta-                                                        dienoate                                                  298    180           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-7-nor-13-                                                             trans,17-cis-prosta-                                                           dienoate                                                  299    181           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-13-                                                             trans,17-cis-prosta-                                                           dienoate                                                  300    182           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-13-trans,17-                                                            cis-prostadienoate                                        301    183           Butyl 9-oxo-15-hydroxy-                                                        13-trans,17-cis-                                                               prostadienoate                                            302    184           Isopropyl 9-oxo-15-                                                            hydroxy-13-trans,17-                                                           cis-prostadienoate                                        303    185           Methyl 9-oxo-15-hydroxy-                                                       13-trans,17-cis-                                                               prostadienoate                                            304    186           n-decyl 9-oxo-15-                                                              hydroxy-13-trans,17-                                                           cis-prostadienoate                                        305    187           Ethyl 9-oxo-15-hydroxy-                                                        5,6,7-trinor-19-iso-                                                           butyl-13-trans,18-                                                             prostadienoate                                            306    188           Ethyl 9-oxo-15-hydroxy-                                                        5,6,7,19,20-pentanor-                                                          13-trans,17-prosta-                                                            dienoate                                                  307    189           Ethyl 9-oxo-15-hydroxy-                                                        19,20-dinor-13-trans,                                                          18-prostadienoate                                         308    190           Ethyl 9-oxo-15-hydroxy-                                                        17-methyl-20-isopro-                                                           penyl-13-trans-prosta-                                                         dienoate                                                  309    191           Ethyl 9-oxo-15-hydroxy-                                                        16-ethyl-6,7,19,20-                                                            tetranor-13-trans-                                                             prostenoate                                               310    192           Ethyl 9-oxo-15-hydroxy-                                                        18,19-dimethyl-6,7-                                                            dinor-13-trans,18-                                                             prostadienoate                                            311    193           Ethyl 9-oxo-15-hydroxy-                                                        16-ethyl-7a,7b-bishomo-                                                        13-trans-prostenoate                                      312    194           Ethyl 9-oxo-15-hydroxy-                                                        19-methyl-7a,7b-bis-                                                           homo-13-trans,18-                                                              prostadienoate                                            313    195           Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-19,20-dinor-                                                           13-trans-prostenoate                                      314    196           Ethyl 9-oxo-15-hydroxy-                                                        2,20-diethyl-13-trans-                                                         prostenoate                                               315    197           Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-16-methyl-20-                                                          nor-trans-prostenoate                                     316    198           Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-18,19-dimethyl-                                                        13-trans,18-prosta-                                                            dienoate                                                  317    199           Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-18,19,20-                                                         trinor-13-trans-                                                               prostenoate                                               318    200           Ethyl 9-oxo-15-hydroxy-                                                        3,3,20-trimethyl-13-                                                           trans-prostenoate                                         319    201           Ethyl 9-oxo-15-hydroxy-                                                        3,3,16-trimethyl-20-                                                           nor-13-trans-prosta-                                                           noate                                                     320    202           Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-19-iso-                                                           butyl-13-trans,18-                                                             prostadienoate                                            321    203           Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-19,20-                                                            dinor-13-trans,17-                                                             prostadienoate                                            322    204           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-20-nor-13-trans-                                                         prostenoate                                               323    205           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-20-methyl-13-                                                            trans-prostenoate                                         324    206           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-16-ethyl-13-                                                             trans-prostenoate                                         325    207           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-16-methyl-20-                                                            nor-13-trans-                                                                  prostenoate                                               326    208           Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-19,20-dinor-13-                                                          trans,17-prostadienoate                                   327    209           Ethyl 9-oxo-15-hydroxy-                                                        7,19,20-trinor-13-                                                             trans,17-prostadienoate                                   328    210           Ethyl 9-oxo-15-hydroxy-                                                        7-nor-18,19-dimethyl-                                                          13-trans,18-prosta-                                                            dienoate                                                  329    211           Ethyl 9-oxo-15-hydroxy-                                                        7,18,19,20-tetranor-                                                           16-methyl-13-trans-                                                            prostenoate                                               330    212           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-20-nor-13-                                                            trans-prostenoate                                         331    213           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-20-ethyl-13-                                                          trans-prostenoate                                         332    214           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-16-ethyl-19,                                                          20-dinor-13-trans-                                                             prostenoate                                               333    215           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-16-methyl-20-                                                         nor-13-trans-prostenoate                                                       prostenoate                                               334    216           Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-19-methyl-13-                                                         trans,18-prostadienoate                                   335    217           Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-18,19-dimethyl-                                                        13-trans,18-prosta-                                                            dienoate                                                  336    218           Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-19,20-dinor-                                                           13-trans,17-prosta-                                                            dienoate                                                  337    219           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-20-nor-13-                                                            trans-prostenoate                                         338    220           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-20-ethyl-13-                                                          trans-prostenoate                                         339    221           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-16-ethyl-13-                                                          trans-prostenoate                                         340    222           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-16-methyl-18,                                                         19,20-trinor-13-trans-                                                         prostenoate                                               341    223           Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-18,19-di-                                                             methyl-13-trans,18-pro-                                                        stadienoate                                               342    224           Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-20-nor-13-                                                            trans-prostenoate                                         343    225           Ethyl 9-oxo-15-hydroxy-                                                        2,20-dimethyl-13-trans-                                                        prostenoate                                               344    226           Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-16-ethyl-19,                                                          20-dinor-13-trans-                                                             prostenoate                                               345    227           Ethyl 9-oxo-15-hydroxy-                                                        2,19-dimethyl-13-trans,                                                        18-prostadienoate                                         346    228           Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-19,20-dinor-                                                          13-trans,17-prosta-                                                            dienoate                                                  347    229           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-20-nor-13-                                                            trans-prostenoate                                         348    230           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-20-methyl-13-                                                         trans-prostenoate                                         349    231           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-16-ethyl-13-                                                          trans-prostenoate                                         350    232           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-18,19-dimethyl-                                                       13-trans,18-prosta-                                                            dienoate                                                  351    233           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-19,20-dinor-                                                          13-trans,17-prosta-                                                            dienoate                                                  352    234           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-5,6,7-trinor-                                                         20-ethyl-13-trans-                                                             prostenoate                                               353    235           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-5,6,7,20-                                                             tetranor-16-methyl-13-                                                         trans-prostenoate                                         354    236           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-5,6,7-trinor-                                                         19-isobutyl-13-trans,                                                          18-prostadienoate                                         355    237           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-20-methyl-13-                                                         trans-prostenoate                                         356    238           Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-19-methyl-13-                                                         trans,18-prostadienoate                                   357    239           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-20-nor-                                                         13-trans-prostenoate                                      358    240           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-20-                                                             ethyl-13-trans-pro-                                                            stenoate                                                  359    241           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-16-                                                             methyl-20-nor-13-trans-                                                        prostenoate                                               360    242           Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-19-                                                             methyl-13-trans,18-                                                            prostadienoate                                            361    243           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-20-nor-13-trans-                                                        prostenoate                                               362    244           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-20-methyl-13-                                                           trans-prostenoate                                         363    245           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-16-ethyl-13-                                                            trans-prostenoate                                         364    246           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-16-methyl-18,19,                                                        20-trinor-13-trans-                                                            prostenoate                                               365    247           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-19-methyl-13-                                                           trans,18-prostadienoate                                   366    248           Ethyl 9-oxo-15-hydroxy-                                                        3-thia-19,20-dinor-13-                                                         trans,17-prostadienoate                                   367    249           Methyl 9-oxo-15-hydroxy-                                                       20-nor-5-cis,13-trans-                                                         prostadienoate                                            368    250           Methyl 9-oxo-15-hydroxy-                                                       20-methyl-5-cis,13-                                                            trans-prostadienoate                                      369    251           Methyl 9-oxo-15-hydroxy-                                                       16-ethyl-5-cis,13-                                                             trans-prostadienoate                                      370    252           Methyl 9-oxo-15-hydroxy-                                                       16-methyl-20-nor-5-cis,                                                        13-trans-prostadienoate                                   371    253           Methyl 9-oxo-15-hydroxy-                                                       19-methyl-5-cis,13-                                                            trans,18-prosta-                                                               trienoate                                                 372    254           Methyl 9-oxo-15-hydroxy-                                                       18,19-dimethyl-5-cis,                                                          13-trans,18-prosta-                                                            trienoate                                                 373    255           Methyl 9-oxo-15-hydroxy-                                                       19,20-dinor-5-cis,13-                                                          trans,17-prosta-                                                               trienoate                                                 374    256           Methyl 9-oxo-15-hydroxy-                                                       5-cis,13-trans,17-cis-                                                         prostatrienoate                                           ______________________________________                                    

EXAMPLES 375-491

Saponification of the alkyl esters designated in the following table by the method described in Example 122 is productive of the prostenoic acids of the table.

                  Table 5                                                          ______________________________________                                               Starting alkyl 9-                                                                            Product                                                    Ex-   oxo-prostenoate                                                                              9-Oxo-15-hydroxy-13-                                       ample of example    trans-prostenoic acid                                      ______________________________________                                         375   258           9-oxo-15-hydroxy-5,6,7-                                                        trinor-13-trans-pros-                                                          tenoic acid                                                376   259           9-oxo-15-hydroxy-7a,7b-                                                        bishomo-13-trans-pros-                                                         tenoic acid                                                377   260           9-oxo-15-hydroxy-2-                                                            ethyl-13-trans-pros-                                                           tenoic acid                                                378   261           9-oxo-15-hydroxy-3,3-                                                          dimethyl-13-trans-                                                             prostenoic acid                                            379   262           9-oxo-15-hydroxy-3-oxa-                                                        13-trans-prostenoic                                                            acid                                                       380   263           9-oxo-15-hydroxy-7-nor-                                                        13-trans-prostenoic                                                            acid                                                       381   264           9-oxo-15-hydroxy-2-                                                            fluoro-13-trans-pros-                                                          tenoic acid                                                382   265           9-oxo-15-hydroxy-7a-                                                           homo-13-trans-pros-                                                            tenoic acid                                                383   266           9-oxo-15-hydroxy-2-                                                            phenyl-13-trans-pros-                                                          tenoic acid                                                384   267           9-oxo-15-hydroxy-2-                                                            methyl-13-trans-pros-                                                          tenoic acid                                                385   268           9-oxo-15-hydroxy-10a-                                                          homo-13-trans-pros-                                                            tenoic acid                                                386   269           9-oxo-15-hydroxy-10a-                                                          homo-5,6,7-trinor-13-                                                          trans-prostenoic acid                                      387   270           9-oxo-15-hydroxy-10a-                                                          homo-7-nor-13-trans-                                                           prostenoic acid                                            388   271           9-oxo-15-hydroxy-7a,-                                                          10a-bishomo-13-trans-                                                          prostenoic acid                                            389   272           9-oxo-15-hydroxy-3-                                                            thia-13-trans-pros-                                                            tenoic acid                                                390   273           9-oxo-15-hydroxy-13-                                                           trans-prostenoic acid                                      391   274           9-oxo-15-hydroxy-13-                                                           trans-prostenoic acid                                      392   275           9-oxo-15-hydroxy-13-                                                           trans-prostenoic acid                                      393   276           9-oxo-15-hydroxy-13-                                                           trans-prostenoic acid                                      394   277           9-oxo-15-hydroxy-5-cis,                                                        13-trans-prostadienoic                                                         acid                                                       395   278           9-oxo-15-hydroxy-20-nor-                                                       13-trans-prostenoic                                                            acid                                                       396   279           9-oxo-15-hydroxy-20-                                                           methyl-13-trans-pros-                                                          tenoic acid                                                397   280           9-oxo-15-hydroxy-16-                                                           ethyl-13-trans-pros-                                                           tenoic acid                                                398   281           9-oxo-15-hydroxy-16-                                                           methyl-20-nor-13-trans-                                                        prostenoic acid                                            399   282           9-oxo-15-hydroxy-19-                                                           methyl-13-trans,18-                                                            prostadienoic acid                                         400   283           9-oxo-15-hydroxy-18,19-                                                        dimethyl-13-trans,18-                                                          prostadienoic acid                                         401   284           9-oxo-15-hydroxy-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                               402   285           9-oxo-15-hydroxy-5,6,7-                                                        trinor-13-trans,17-cis-                                                        prostadienoic acid                                         403   286           9-oxo-15-hydroxy-6,7-di-                                                       nor-13-trans,17-cis-                                                           prostadienoic acid                                         404   287           9-oxo-15-hydroxy-7a,7b-                                                        bishomo-13-trans,17-                                                           cis-prostadienoic acid                                     405   288           9-oxo-15-hydroxy-2-                                                            ethyl-13-trans,17-cis-                                                         prostadienoic acid                                         406   289           9-oxo-15-hydroxy-3,3-                                                          dimethyl-13-trans,17-                                                          cis-prostadienoic acid                                     407   290           9-oxo-15-hydroxy-3-oxa-                                                        13-trans,17-cis-pros-                                                          tadienoic acid                                             408   291           9-oxo-15-hydroxy-7-nor-                                                        13-trans,17-cis-pros-                                                          tadienoic acid                                             409   292           9-oxo-15-hydroxy-2-                                                            fluoro-13-trans,17-cis-                                                        prostadienoic acid                                         410   293           9-oxo-15-hydroxy-7a-                                                           homo-13-trans,17-cis-                                                          prostadienoic acid                                         411   294           9-oxo-15-hydroxy-2-                                                            phenyl-13-trans,17-cis-                                                        prostadienoic acid                                         412   295           9-oxo-15-hydroxy-2-                                                            methyl-13-trans,17-                                                            cis-prostadienoic acid                                     413   296           9-oxo-15-hydroxy-10a-                                                          homo-13-trans,17-cis-                                                          prostadienoic acid                                         414   297           9-oxo-15-hydroxy-10a-                                                          homo-5,6,7-trinor-13-                                                          trans,17-cis-prosta-                                                           dienoic acid                                               415   298           9-oxo-15-hydroxy-10a-                                                          homo-7-nor-13-trans,-                                                          17-cis-prostadienoic                                                           acid                                                       416   299           9-oxo-15-hydroxy-7a,-                                                          10a-bishomo-13-trans,-                                                         17-cis-prostadienoic                                                           acid                                                       417   300           9-oxo-15-hydroxy-3-thia-                                                       13-trans,17-cis-prosta-                                                        dienoic acid                                               418   301           9-oxo-15-hydroxy-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                               419   302           9-oxo-15-hydroxy-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                               420   303           9-oxo-15-hydroxy-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                               421   304           9-oxo-15-hydroxy-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                               422   305           9-oxo-15-hydroxy-5,6,7-                                                        trinor-19-isobutyl-13-                                                         trans,18-prostadienoic                                                         acid                                                       423   306           9-oxo-15-hydroxy-5,6,7-                                                        19,20-pentanor-13-trans,                                                       17-prostadienoic acid                                      424   307           9-oxo-15-hydroxy-19,20-                                                        dinor-13-trans,18-                                                             prostadienoic acid                                         425   308           9-oxo-15-hydroxy-17,-                                                          methyl-20-isopropenyl-                                                         13-trans-prostenoic                                                            acid                                                       426   309           9-oxo-15-hydroxy-16-                                                           ethyl-6,7,19,20-tetra-                                                         nor-13-trans-prostenoic                                                        acid                                                       427   310           9-oxo-15-hydroxy-18,19-                                                        dimethyl-6,7-dinor-13-                                                         trans,18-prostadienoic                                                         acid                                                       428   311           9-oxo-15-hydroxy-16-                                                           ethyl-7a,7b-bishomo-                                                           13-trans-prostenoic                                                            acid                                                       429   312           9-oxo-15-hydroxy-19-                                                           methyl-7a,7b-bishomo-                                                          13-trans,18-prosta-                                                            dienoic acid                                               430   313           9-oxo-15-hydroxy-2-                                                            ethyl-19,20-dinor-13-                                                          trans-prostenoic acid                                      431   314           9-oxo-15-hydroxy-2,20-                                                         diethyl-13-trans-pros-                                                         enoic acid                                                 432   315           9-oxo-15-hydroxy-2-                                                            ethyl-16-methyl-20-nor-                                                        13-trans-prostenoic                                                            acid                                                       433   316           9-oxo-15-hydroxy-2-                                                            ethyl-18,19-dimethyl-                                                          13-trans,18-prosta-                                                            dienoic acid                                               434   317           9-oxo-15-hydroxy-3,3-                                                          dimethyl-18,19,20-tri-                                                         nor-13-trans-prostenoic                                                        acid                                                       435   318           9-oxo-15-hydroxy-3,3,-                                                         20-trimethyl-13-trans-                                                         prostenoic acid                                            436   319           9-oxo-15-hydroxy-3,3-                                                          16-trimethyl-20-nor-13-                                                        trans-prostenoic acid                                      437   320           9-oxo-15-hydroxy-3,3-                                                          dimethyl-19-isobutyl-                                                          13-trans,18-prosta-                                                            dienoic acid                                               438   321           9-oxo-15-hydroxy-3,3-                                                          dimethyl-19,20-dinor-                                                          13-trans,17-prosta-                                                            dienoic acid                                               439   322           9-oxo-15-hydroxy-3-oxa-                                                        20-nor-13-trans-prost-                                                         enoic acid                                                 440   323           9-oxo-15-hydroxy-3-oxa-                                                        20-methyl-13-trans-                                                            prostenoic acid                                            441   324           9-oxo-15-hydroxy-3-oxa-                                                        16-ethyl-13-trans-                                                             prostenoic acid                                            442   325           9-oxo-15-hydroxy-3-oxa-                                                        16-methyl-20-nor-13-                                                           trans-prostenoic acid                                      443   326           9-oxo-15-hydroxy-3-oxa-                                                        19,20-dinor-13-trans,-                                                         17-prostadienoic acid                                      444   327           9-oxo-15-hydroxy-7,19-                                                         20-trinor-13-trans,17-                                                         prostadienoic acid                                         445   328           9-oxo-15-hydroxy-7-nor-                                                        18,19-dimethyl-13-                                                             trans,18-prostadienoic                                                         acid                                                       446   329           9-oxo-15-hydroxy-7,18,-                                                        19,20-tetranor-16-meth-                                                        yl-13-trans-prostenoic                                                         acid                                                       447   330           9-oxo-15-hydroxy-2-                                                            fluoro-20-nor-13-trans-                                                        prostenoic acid                                            448   331           9-oxo-15-hydroxy-2-                                                            fluoro-20-ethyl-13-                                                            trans-prostenoic acid                                      449   332           9-oxo-15-hydroxy-2-                                                            fluoro-16-ethyl-19,20-                                                         dinor-13-trans-pros-                                                           tenoic acid                                                450   333           9-oxo-15-hydroxy-2-                                                            fluoro-16-methyl-20-                                                           nor-13-trans-pros-                                                             tenoic acid                                                451   334           9-oxo-15-hydroxy-2-                                                            fluoro-19-methyl-13-                                                           trans,18-prostadienoic                                                         acid                                                       452   335           9-oxo-15-hydroxy-7a-                                                           homo-18,19-dimethyl-                                                           13-trans,18-prosta-                                                            dienoic acid                                               453   336           9-oxo-15-hydroxy-7a-                                                           homo-19,20-dinor-13-                                                           trans,17-prostadienoic                                                         acid                                                       454   337           9-oxo-15-hydroxy-2-                                                            phenyl-20-nor-13-trans-                                                        prostenoic acid                                            455   338           9-oxo-15-hydroxy-2-                                                            phenyl-20-ethyl-13-                                                            trans-prostenoic acid                                      456   339           9-oxo-15-hydroxy-2-                                                            phenyl-16-ethyl-13-                                                            trans-prostenoic acid                                      457   340           9-oxo-15-hydroxy-2-phen-                                                       yl-16-methyl-18,19,20-                                                         trinor-13-trans-pros-                                                          tenoic acid                                                458   341           9-oxo-15-hydroxy-2-                                                            phenyl-18,19-dimethyl-                                                         13-trans,18-prosta-                                                            dienoic acid                                               459   342           9-oxo-15-hydroxy-2-                                                            methyl-20-nor-13-trans-                                                        prostenoic acid                                            460   343           9-oxo-15-hydroxy-2,20-                                                         dimethyl-13-trans-                                                             prostenoic acid                                            461   344           9-oxo-15-hydroxy-2-                                                            methyl-16-ethyl-19,20-                                                         dinor-13-trans-pros-                                                           tenoic acid                                                462   345           9-oxo-15-hydroxy-2,19-                                                         dimethyl-13-trans,18-                                                          prostadienoic acid                                         463   346           9-oxo-15-hydroxy-2-                                                            methyl-19,20-dinor-                                                            13-trans,17-prosta-                                                            dienoic acid                                               464   347           9-oxo-15-hydroxy-10a-                                                          homo-20-nor-13-trans-                                                          prostenoic acid                                            465   348           9-oxo-15-hydroxy-10a-                                                          homo-20-methyl-13-                                                             trans-prostenoic acid                                      466   349           9-oxo-15-hydroxy-10a-                                                          homo-16-ethyl-13-trans-                                                        prostenoic acid                                            467   350           9-oxo-15-hydroxy-10a-                                                          homo-18,19-dimethyl-                                                           13-trans,18-prosta-                                                            dienoic acid                                               468   351           9-oxo-15-hydroxy-10a-                                                          homo-19,20-dinor-13-                                                           trans,17-prostadienoic                                                         acid                                                       469   352           9-oxo-15-hydroxy-10a-                                                          homo-5,6,7-trinor-20-                                                          etyl-13-trans-pros-                                                            tenoic acid                                                470   353           9-oxo-15-hydroxy-10a-                                                          homo-5,6,7,20-tetra-                                                           nor-16-methyl-13-trans-                                                        prostenoic acid                                            471   354           9-oxo-15-hydroxy-10a-                                                          homo-5,6,7-trinor-19-                                                          isobutyl-13-trans,18-                                                          prostadienoic acid                                         472   355           9-oxo-15-hydroxy-10a-                                                          homo-20-methyl-13-                                                             trans-prostenoic acid                                      473   356           9-oxo-15-hydroxy-10a-                                                          homo-19-methyl-13-                                                             trans,18-prostadienoic                                                         acid                                                       474   357           9-oxo-15-hydroxy-7a,10a-                                                       bishomo-20-nor-13-                                                             trans-prostenoic acid                                      475   358           9-oxo-15-hydroxy-7a,10a-                                                       bishomo-20-ethyl-13-                                                           trans-prostenoic acid                                      476   359           9-oxo-15-hydroxy-7a,10a-                                                       bishomo-16-methyl-20-                                                          nor-13-trans-prostenoic                                                        acid                                                       477   360           9-oxo-15-hydroxy-7a,10a-                                                       bishomo-19-methyl-13-                                                          trans,18-prostadienoic                                                         acid                                                       478   361           9-oxo-15-hydroxy-3-thia-                                                       20-nor-13-trans-pros-                                                          tenoic acid                                                479   362           9-oxo-15-hydroxy-3-thia-                                                       20-methyl-13-trans-                                                            prostenoic acid                                            480   363           9-oxo-15-hydroxy-3-thia-                                                       16-ethyl-13-trans-                                                             prostenoic acid                                            481   364           9-oxo-15-hydroxy-3-thia-                                                       16-methyl-18,19,20-                                                            trinor-13-trans-pros-                                                          tenoic acid                                                482   365           9-oxo-15-hdroxy-3-thia-                                                        19-methyl-13-trans,18-                                                         prostadienoic acid                                         483   366           9-oxo-15-hydroxy-3-thia-                                                       19,20-dinor-13-trans,-                                                         17-prostadienoic acid                                      484   367           9-oxo-15-hydroxy-20-nor-                                                       5-cis,13-trans-prosta-                                                         dienoic acid                                               485   368           9-oxo-15-hydroxy-20-                                                           methyl-5-cis,13-trans-                                                         prostadienoic acid                                         486   369           9-oxo-15-hydroxy-16-                                                           ethyl-5-cis,13-trans-                                                          prostadienoic acid                                         487   370           9-oxo-15-hydroxy-16-                                                           methyl-20-nor-5-cis,13-                                                        trans-prostadienoic                                                            acid                                                       488   371           9-oxo-15-hydroxy-19-                                                           methyl-5-cis,13-trans,-                                                        18-prostatrienoic acid                                     489   372           9-oxo-15-hydroxy-18,19-                                                        dimethyl-5-cis,13-                                                             trans-18-prostatrienoic                                                        acid                                                       490   373           9-oxo-15-hydroxy-19,20-                                                        dinor-5-cis,13-trans,-                                                         17-prostatrienoic acid                                     491   374           9-oxo-15-hydroxy-5-cis,-                                                       13-trans,17-cis-prosta-                                                        trienoic acid                                              ______________________________________                                    

EXAMPLE 492 Preparation of 3-(tert-butoxy)-1-iodooctane

Into a solution of 16.7 g. of 1-iodo-3-octanol [Shriner et at., J. Org. Chem. 4, 103 (1939)] in 250 ml. of methylene chloride is bubbled isobutylene at a fast rate until the solution is saturated. The solution is cooled and 2 ml. of concentrated sulfuric acid is added. The solution is stoppered and allowed to stand at room temperature for 3 days. After the solution is poured into 300 ml. of 5% sodium carbonate, the organic phase is separated, washed with brine, dried with anhydrous magnesium sulfate and evaporated to dryness. Distillation gave 13.9 g. (68%) of proudct, b.p. 59° C. (0.008 mm).

EXAMPLE 493 Preparation of 15-(tert-butoxy)-9-oxoprostanoic acid, ethyl ester

To a Grignard solution, prepared from 5.05 g. of magnesium and 65.8 g. of 3-(tert-butoxy)-1-iodooctane in 150 ml. of diethyl ether under nitrogen atmosphere, is added 4.0 g. of copper iodide-tri-n-butylphosphine complex followed by dropwise addition of 49 g. of 2-(6-carbethoxyhexyl)cyclopent-2-en-1-one [Hardegger et al., Helv. Chim. Acta 50, 2501 (1967)] and the resulting mixture is stirred for 18 hours. Saturated ammonium chloride (110 ml.) is added followed by 100 ml. of water and 100 ml. of diethyl ether. Unreacted magnesium is removed by filtration. The ethereal layer is washed successively with aqueous sodium thiosulfate solution, ammonium chloride solution, and water, dried over magnesium sulfate and taken to dryness to give an oil. Distillation at 0.05 mm. (bath 100°-185° C.) gives 45.5 g. of material containing unreacted starting material and 30 g. (85% yield based on non-recovered starting material; see below) of residue which contains the desired product. This material is chromatographed on silica gel. The product is eluted with diethyl ether to give 25.2 g. (71% based on recovered starting material) of a syrup; this material has no significant ultraviolet absorption; λ_(max) ^(KBr) 5.74, 7.20, 7.35, 8.35 μ; nmr 2H quartet δ4.09 (OCH₂ of ester), 1H broad singlet 3.57 (carbinolic proton), 5H overlapping multiplets 2.0-2.4 (protons next to C=O), 3H triplet 1.22 (CH₃ of ethyl), 9H singlet 1.17 (CH₃ 's to t-butyl) and 3H triplet 0.9 (terminal methyl); mass spectrum: m/e 424.

EXAMPLE 494 Preparation of 15-hydroxy-9-oxoprostanoic acid, ethyl ester

A solution of 25 g. of 15-(tert-butoxy)-9-oxoprostanoic acid, ethyl ester in 100 ml. of trifluoroacetic acid is stirred in an ice bath for 1 hour and is then poured into 500 ml. of ice water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrousmagnesium sulfate, and taken to dryness. The resulting oil is dissolved in 200 ml. of 1N ammonium hydroxide in ethanol, kept at ambient temperature for 15 minutes, then taken to dryness. The residual oil is dissolved in chloroform and washed with 1N hydrochloric acid, saturated sodium chloride solution, dried and taken to dryness to give 21.7 g. (100%) of product as a yellow syrup. There is essentially no uv absorption; λ_(max) ^(KBr) 2.90, 5.75, 8.45 μ; nmr 2H quartet δ4.13 (OCH₂ of ester), 1H broad singlet 3.63 (carbinolic proton), 3H triplet (CH₃ of ester), and 3H distorted triplet 0.92 (terminal methyl); mass spectrum: m/e 368.

EXAMPLE 495 Preparation of 15-hydroxy-9-oxoprostanoic acid

A suspension of 15 g. of 15-hydroxy-9-oxoprostanoic acid, ethyl ester in 230 ml. of aqueous methanol (1:1) containing 6.45 g. of potassium hydroxide is stirred at 50° C. for 1 hour and then at room temperature for 18 hours. The resulting solution is acidified with 1N hydrochloric acid, saturated with sodium chloride, and extracted several times with diethyl ether. The combined ether extracts are washed twice with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and taken to dryness to give 13.1 g. (94%) of product as an oil. There is essentially no uv absorption; [α]_(D) ²⁵ 0° (1.0% in CHCl₃); λ_(max) ^(KBr) 2.80-3.70 (broad), 5.75, 5.87 μ; nmr 2H singlet δ 6.05 (hydroxyl and carboxyl protons), 1H broad singlet 3.63 (carbinolic proton), and 3H distorted triplet 0.93 (terminal methyl); mass spectrum: m/e 340.

EXAMPLE 496 Preparation of 1-chloro-3-hydroxy-4-octyne

To 68 ml. of 1.6M butyllithium in hexane at -50° C. is added dropwise, with stirring, 7.4 g. of 1-pentyne. The resulting white sludge is diluted with 20 ml. of hexane, brought to 10° C. and treated with 11 g. of freshly prepared β-chloropropionaldehyde (Org. Syn., Coll. Vol. I, p. 166) at such a rate that the temperature is maintained at 10°-15° C. The solution is allowed to stir at ambient temperature for 18 hours then treated with saturated ammonium chloride solution. The organic phase is separated, washed with dilute hydrochloric solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives 5.1 g. of product b.p. 65°-66° C. at 0.3 nm.; λmax. 2.95 (--OH) and 4.55 μ (--C.tbd.C--); vapor phase chromatography shows one peak.

EXAMPLE 497 Preparation of 1-chloro-3-hydroxy-4-cis-octene

A solution of 2g. of 1-chloro-3-hydroxy-4-octyne (Example 496) is hydrogenated in 50 ml. absolute alcohol using 200 mg. of Lindlar catalyst (5% Pd on CaCO₃). The catalyst is removed by filtration and the mother liquor is taken to dryness to give 2 g. of an oil; λ max. 2.95 (--OH) and 7.25 μ ##STR37##

EXAMPLE 498 Preparation of 3-hydroxy-1-iodo-4-octyne

A mixture of 15 g. of sodium iodide in 100 ml. of 2-butanone is stirred at the reflux temperature for 30 minutes. To the cooled mixture is added 12 g. of 1-chloro-3-hydroxy-4-octyne in 150 ml. of 2-butanone. The resulting mixture is stirred at the reflux temperature for 18 hours then cooled and filtered. The mother liquor is taken to dryness and the residue is triturated with benzene and filtered. The benzene is taken to dryness to give the subject product as an oil. The material is shown to be homogeneous by vapor phase chromatography and thin layer chromatography.

EXAMPLE 499 Preparation of 3-hydroxy-1-iodo-4-cis-octen

The subject compound is prepared from 3-hydroxy-1-chloro-4-cis-octene and sodium iodide by the method of Example 498.

EXAMPLE 500 Preparation of 3-t-butoxy-1-iodo-4-octyne

The subject compound is prepared from 3-hydroxy-1-iodo-4-octyne (Example 498) and isobutylene by the method of Example 492.

EXAMPLE 501 Preparation of 3-t-butoxy-1-iodo-4-cis-octene

The subject cpompound is prepared from 3-hydroxy-1-iodo-4-cis-octene (Example 499) and isobutylene by the method of Example 492.

EXAMPLE 502 Preparation of 3-(tert-butoxy)-1-iodohexane

A mixture of 23.4 g. of 1-chloro-3-hexanol [Fourneau, et. al., Bull. Soc. Chem. France, 25, 367 (1919)] in 300 ml. of 2-butanone containing 30 g. of sodium iodide is stirred at the reflux temperature for 18 hours. The cooled solution is filtered and the mother liquor is taken to dryness. Distillation of the residue affords 32.9 g. (84%) of 1-iodo-3-hexanol, b.p. 105° C. (10 mm). Treatment of this material in 500 ml. of methylene chloride, containing 4 ml. of concentrated sulfuric acid, with isobutylene according to the procedure described in Example 492 gives 27 g. of crude material. Chromatography on florisil affords 16 g. of product; λmax. 7.22 and 7.34 μ (tert-butyl group).

EXAMPLES 503-558

Treatment of the cyclopentenones designated in the table below with the designated Grignard reagents by the procedure of Example 493 is productive of the alkyl 9-oxo-15-t-butoxy-8ξ-prostanoates and prostenoates of the table. 3-t-Butoxyoctylmagnesium iodide was prepared from 3-t-butoxy-1-iodooctane (Example 492); 3-t-butoxyhexyl magnesium iodide was prepared from 3t-butoxy-1-iodohexane (Example 502), 3-t-butoxy-4-octynyl magnesium iodide was prepared from 3-t-butoxy-1-iodo-4-octyne (Example 500); and 3-t-butoxy-4-cis-octenyl magnesium iodide was prepared from 3-t-butoxy-1-iodo-4-cis-octene (Example 501).

                                      Table 8                                      __________________________________________________________________________          Starting cyclopentenone                                                                               Product Alkyl 9-Oxo-15-t-butoxy-8ξ-prostano                                 ates,                                              Example                                                                             of Example   Girgnard Reagent                                                                         prostynoates and prostenoates                      __________________________________________________________________________     503  31           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-2-ethyl-8ξ-prostano                                 ate                                                                  magnesium iodide                                             504  41           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-3,3-dimethyl-8ξ-                          magnesium iodide                                                                         prostanoate                                        505  46           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-3-oxa-8ξ-prostanoat                                 e                                                                    magnesium iodide                                             506  70           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-2-fluoro-8ξ-prostan                                 oate                                                                 magnesium iodide                                             507  79           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-2-phenyl-8ξ-prostan                                 oate                                                                 magnesium iodide                                             508  99           3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-2-methyl-8ξ-prostan                                 oate                                                                 magnesium iodide                                             509  118          3-t-butoxyoctyl                                                                          ethyl 9-oxo-15-t-butoxy-3-thia-8ξ-prostanoa                                 te                                                                   magnesium iodide                                             510  900          3-t-butoxyoctyl                                                                          methyl 9-oxo-15-t-butoxy-8ξ-5-cis-prostenoa                                 te                                                                   magnesium iodide                                             511  31           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-2-ethyl-19,20-dinor-8.                                 xi.-                                                                 magnesium iodide                                                                         prostanoate                                        512  41           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-3,3-dimethyl-19,20-                          magnesium iodide                                                                         dinor-8ξ-prostanoate                            513  46           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-3-oxa-19,20-dinor-8.xi                                 .-                                                                   magnesium iodide                                                                         prostanoate                                        514  70           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-2-fluoro-19,20-dinor-8                                 ξ-                                                                magnesium iodide                                                                         prostanoate                                        515  79           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-2-phenyl-19,20-dinor-8                                 ξ-                                                                magnesium iodide                                                                         prostanoate                                        516  99           3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-2-methyl-19,20-dinor-8                                 ξ-                                                                magnesium iodide                                                                         prostanoate                                        517  118          3-t-butoxyhexyl                                                                          ethyl 9-oxo-15-t-butoxy-3-thia-19,20-dinor-8.x                                 i.-                                                                  magnesium iodide                                                                         prostanoate                                        518  900          5-t-butoxyhexyl                                                                          methyl 9-oxo-15-t-butoxy-19,20-dinor-8ξ-5-c                                 is-                                                                  magnesium iodide                                                                         prostenoate                                        519  13           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-8ξ-16-prostynoate                         ynyl magnesium                                                                 iodide                                                       520  15           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-6,7-dinor-8ξ-16-                          ynyl magnesium                                                                           prostynoate                                                          iodide                                                       521  23           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-7a,7b-bishomo-8ξ-16                                 -                                                                    ynyl magnesium                                                                           prostynoate                                                          iodide                                                       522  31           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-2-ethyl-8ξ-16-prost                                 ynoate                                                               ynyl magnesium                                                                 iodide                                                       523  41           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-3,3-dimethyl-8ξ-16-                                 N                                                                    ynyl magnesium                                                                           prostynoate                                                          iodide                                                       524  46           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-3-oxa-8ξ-16-prostyn                                 oate                                                                 ynyl magnesium                                                                 iodide                                                       525  53           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-7-nor-8ξ-16-prostyn                                 oate                                                                 ynyl magnesium                                                                 iodide                                                       526  70           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-2-fluoro-8ξ-16-pros                                 tynoate                                                              ynyl magnesium                                                                 iodide                                                       527  74           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-7a-homo-8ξ-16-prost                                 ynoate                                                               ynyl magnesium                                                                 iodide                                                       528  79           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-2-phenyl-8ξ-16-pros                                 tynoate                                                              ynyl magnesium                                                                 iodide                                                       529  81           3-t-butoxy-4-oct-                                                                        butyl 9-oxo-15-t-butoxy-8ξ-16-prostynoate                         ynyl magnesium                                                                 iodide                                                       530  82           3-t-butoxy-4-oct-                                                                        isopropyl 9-oxo-15-t-butoxy-8ξ-16-prostynoa                                 te                                                                   ynyl magnesium                                                                 iodide                                                       531  83           3-t-butoxy-4-oct-                                                                        methyl 9-oxo-15-t-butoxy-8ξ-16-prostynoate                                  N                                                                    ynyl magnesium                                                                 iodide                                                       532  84           3-t-butoxy-4-oct-                                                                        decyl 9-oxo-15-t-butoxy-8ξ-16-prostynoate                         ynyl magnesium                                                                 iodide                                                       533  99           3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-2-methyl-8ξ-16-pros                                 tynoate                                                              ynyl magnesium                                                                 iodide                                                       534  118          3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-3-thia-8ξ-16-prosty                                 noate                                                                ynyl magnesium                                                                 iodide                                                       535  111          3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-10a-homo-8ξ-16-pros                                 tynoate                                                              ynyl magnesium                                                                 iodide                                                       536  113          3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-10a-homo-7-nor-8ξ-1                                 6-                                                                   ynyl magnesium                                                                           prostynoate                                                          iodide                                                       537  114          3-t-butoxy-4-oct-                                                                        ethyl 9-oxo-15-t-butoxy-7a,10a-bishomo-8ξ-1                                 6-                                                                   ynyl magnesium                                                                           prostynoate                                                          iodide                                                       538  900          3-t-butoxy-4-oct-                                                                        methyl 9-oxo-15-t-butoxy-8ξ-16-yne-5-cis-                         ynyl magnesium                                                                           prostenoate                                                          iodide                                                       539  13           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-8ξ-16-cis-prostenoa                                 te                                                                   octenyl magnesium                                                              iodide                                                       540  15           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-6,7-dinor-8ξ-16-cis                                 -                                                                    octenyl magnesium                                                                        prostenoate                                                          iodide                                                       541  23           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-7a,7b-bishomo-8ξ-16                                 -                                                                    octenyl magnesium                                                                        cis-prostenoate                                                      iodide                                                       542  31           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-2-ethyl-8ξ-16-cis-                                  S                                                                    octenyl magnesium                                                                        prostenoate                                                          iodide                                                       543  41           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-3,3-dimethyl-8ξ-16-                                 cis-                                                                 octenyl magnesium                                                                        prostenoate                                                          iodide                                                       544  46           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-3-oxa-8ξ-16-cis-                          octenyl magnesium                                                                        prostenoate                                                          iodide                                                       545  53           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-7-nor-8ξ-16-cis-                          octenyl magnesium                                                                        prostenoate                                                          iodide                                                       546  70           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-2-fluoro-8ξ-16-cis-                       octenyl magnesium                                                                        prostenoate                                                          iodide                                                       547  74           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-7a-homo-8ξ-16-cis-                        octenyl magnesium                                                                        prostenoate                                                          iodide                                                       548  79           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-2-phenyl-8ξ-16-cis-                                 N                                                                    octenyl magnesium                                                                        prostenoate                                                          iodide                                                       549  81           3-t-butoxy-4-cis-                                                                        butyl 9-oxo-15-t-butoxy-8Ξ-16-cis-prostenoa                                 te                                                                   octenyl magnesium                                                              iodide                                                       550  82           3-t-butoxy-4-cis-                                                                        isopropyl 9-oxo-15-t-butoxy-8ξ-16-cis-                            octenyl magnesium                                                                        prostenoate                                                          iodide                                                       551  83           3-t-butoxy-4-cis-                                                                        methyl 9-oxo-15-t-butoxy-8ξ-16-cis-                               octenyl magnesium                                                                        prostenoate                                                          iodide                                                       552  84           3-t-butoxy-4-cis-                                                                        decyl 9-oxo-15-t-butoxy-8ξ-16-cis-prostenoa                                 te                                                                   octenyl magnesium                                                              iodide                                                       553  99           3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-2-methyl-8ξ-16-cis-                       octenyl magnesium                                                                        prostenoate                                                          iodide                                                       554  118          3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-3-thia-8ξ-16-cis-                         octenyl magnesium                                                                        prostenoate                                                          iodide                                                       555  111          3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-10a-homo-8ξ-16-cis-                       octenyl magnesium                                                                        prostenoate                                                          iodide                                                       556  113          3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-10a-homo-7-nor-8ξ-1                                 6-                                                                   octenyl magnesium                                                                        cis-prostenoate                                                      iodide                                                       557  114          3-t-butoxy-4-cis-                                                                        ethyl 9-oxo-15-t-butoxy-7a,10a-bishomo-8ξ-1                                 6-                                                                   octenyl magnesium                                                                        cis-prostenoate                                                      iodide                                                       558  900          3-t-butoxy-4-cis-                                                                        methyl 9-oxo-15-t-butoxy-8ξ-5-cis-16-cis-                         octenyl magnesium                                                                        prostadienoate                                                       iodide                                                       __________________________________________________________________________

EXAMPLES 559-614

Treatment of the 9-oxo-15-t-butoxy derivatives designated in the table below with trifluoroacetic acid and then with aqueous ammonia by the method described in Example 494 is productive of the 9-oxo-15-hydroxy esters of the table.

                  TABLE 7                                                          ______________________________________                                               Starting 15-t-                                                           Ex-   butoxy derivative                                                                             Product Alkyl 9-oxo-15-                                   ample of Example     hydroxy derivative                                        ______________________________________                                         559   503            Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-prostanoate                                       560   504            Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-prostano-                                                         ate                                                       561   505            Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-prostanoate                                         562   506            Ethyl 9-oxo-15-hydroxy                                                         2-fluoro-prostanoate                                      563   507            Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-prostanoate                                      564   508            Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-prostanoate                                      565   509            Ethyl 9-oxo-15-hydroxy-                                                        3-thia-prostanoate                                        566   510            Methyl 9-oxo-15-hydroxy-                                                       5-cis-prostenoate                                         567   511            Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-19,20-dinor-                                                           prostanoate                                               568   512            Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-19,20-                                                            dinor-prostanoate                                         569   513            Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-1,920-dinor-                                                             prostanoate                                               570   514            Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-19,20-dinor-                                                          prostanoate                                               571   515            Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-19,20-dinor-                                                          prostanoate                                               572   516            Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-19,20-dinor-                                                          prostanoate                                               573   517            Ethyl 9-oxo-15-hydroxy-                                                        3-thia-19,20-dinor-                                                            prostanoate                                               574   518            Methyl 9-oxo-15-hydroxy-                                                       19,20-dinor-5-cis-                                                             prostenoate                                               575   519            Ethyl 9-oxo-15-hydroxy-                                                        16-prostynoate                                            576   520            Ethyl 9-oxo-15-hydroxy-                                                        6,7-dinor-16-prostyno-                                                         ate                                                       577   521            Ethyl 9-oxo-15-hydroxy-                                                        7a,7b-bishomo-16-prost-                                                        ynoate                                                    578   522            Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-16-prostynoate                                    579   523            Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-16-prost-                                                         ynoate                                                    580   524            Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-16-prostynoate                                      581   525            Ethyl 9-oxo-15-hydroxy-                                                        7-nor-16-prostynoate                                      582   526            Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-16-prostynoate                                   583   527            Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-16-prostynoate                                    584   528            Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-16-prostynoate                                   585   529            Butyl 9-oxo-15-hydroxy-                                                        16-prostynoate                                            586   530            Isopropyl 9-oxo-15-hy-                                                         droxy-16-prostynoate                                      587   531            Methyl 9-oxo-15-hydroxy-                                                       16-prostynoate                                            588   532            Decyl 9-oxo-15-hydroxy-                                                        16-prostynoate                                            589   533            Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-16-prostynoate                                   590   534            Ethyl 9-oxo-15-hydroxy-                                                        3-thia-16-prostynoate                                     591   535            Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-16-prostynoate                                   592   536            Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-7-nor-16-                                                             prostynoate                                               593   537            Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-16-                                                             prostynoate                                               594   538            Methyl 9-oxo-15-hydroxy-                                                       16-yne-5-cis-prostenoate                                  595   539            Ethyl 9-oxo-15-hydroxy-                                                        16-cis-prostenoate                                        596   540            Ethyl 9-oxo-15-hydroxy-                                                        6,7-dinor-16-cis-pros-                                                         tenoate                                                   597   541            Ethyl 9-oxo-15-hydroxy-                                                        7a,7b-bishomo-16-cis-                                                          prostenoate                                               598   542            Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-16-cis-prosteno-                                                       ate                                                       599   543            Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-16-cis-                                                           prostenoate                                               600   544            Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-16-cis-prostenoate                                  601   545            Ethyl 9-oxo-15-hydroxy-                                                        7-nor-16-cis-prostenoate                                  602   546            Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-16-cis-prosten-                                                       oate                                                      603   547            Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-16-cis-prosten-                                                        oate                                                      604   548            Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-16-cis-prosten-                                                       oate                                                      605   549            Butyl 9-oxo-15-hydroxy-                                                        16-cis-prostenoate                                        606   550            Isopropyl 9-oxo-15-hy-                                                         droxy-16-cis-prostenoate                                  607   551            Methyl 9-oxo-15-hydroxy-                                                       16-cis-prostenoate                                        608   552            Decyl 9-oxo-15-hydroxy-                                                        16-cis-prostenoate                                        609   553            Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-16-cis-pros-                                                          tenoate                                                   610   554            Ethyl 9-oxo-15-hydroxy-                                                        3-thia-16-cis-prosteno-                                                        ate                                                       611   555            Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-16-cis-pros-                                                          tenoate                                                   612   556            Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-7-nor-16-cis-                                                         prostenoate                                               613   557            Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-16-cis-                                                         prostenoate                                               614   558            Methyl 9-oxo-15-hydroxy-                                                       5-cis-16-cis-prostadi-                                                         enoate                                                    ______________________________________                                    

EXAMPLES 615-662

Saponification of the 9-oxo-15-hydroxy alkyl esters designated in the table below by the procedure described in Example 495 is productive of the carboxylic acids of the table.

                  TABLE 8                                                          ______________________________________                                                Starting alkyl                                                          Ex-    ester of     Product 9-oxo-15-hydroxy-                                  ample  Example      prostanoic acid                                            ______________________________________                                         615    559          9-oxo-15-hydroxy-2-ethyl-                                                      prostanoic acid                                            616    560          9-oxo-15-hydroxy-3,3-di-                                                       methyl-prostanoic acid                                     617    561          9-oxo-15-hydroxy-3-oxa-                                                        prostanoic acid                                            618    562          9-oxo-15-hydroxy-2-fluoro-                                                     prostanoic acid                                            619    563          9-oxo-15-hydroxy-2-phenyl-                                                     prostanoic acid                                            620    564          9-oxo-145-hydroxy-2-methyl-                                                    prostanoic acid                                            621    565          9-oxo-15-hydroxy-3-thia-                                                       prostanoic acid                                            622    566          9-oxo-15-hydroxy-5-cis-                                                        prostenoic acid                                            623    567          9-oxo-15-hydroxy-2-ethyl-                                                      19,20-dinor-prostanoic                                                         acid                                                       624    568          9-oxo-15-3,3-dimethyl-19,                                                      20-dinor-prostanoic acid                                   625    569          9-oxo-15-hydroxy-3-oxa-                                                        19,20-dinor-prostanoic                                                         acid                                                       626    570          9-oxo-15-hydroxy-2-fluoro-                                                     19,20-dinor-prostanoic                                                         acid                                                       627    571          9-oxo-15-hydroxy-2-phenyl-                                                     19,20-dinor-prostanoic                                                         acid                                                       628    572          9-oxo-15-hydroxy-2-methyl-                                                     19,20-dinor-prostanoic                                                         acid                                                       629    573          9-oxo-15-hydroxy-3-thia-                                                       19,20-dinor-prostanoic                                                         acid                                                       630    574          9-oxo-15-hydroxy-19,20-                                                        dinor-5-cis-prostenoic acid                                631    575          9-oxo-15-hydroxy-16-pros-                                                      tynoic acid                                                632    576          9-oxo-15-hydroxy-6,7-dinor-                                                    16-prostynoic acid                                         633    577          9-oxo-15-hydroxy-7a,7b-bis-                                                    homo-16-prostynoic acid                                    634    578          9-oxo-15-hydroxy-2-ethyl-                                                      16-prostynoic acid                                         635    579          9-oxo-15-hydroxy-3,3-di-                                                       methyl-16-prostynoic acid                                  636    580          9-oxo-15-hydroxy-3-oxa-16-                                                     prostynoic acid                                            637    581          9-oxo-15-hydroxy-7-nor-16-                                                     prostynoic acid                                            638    582          9-oxo-15-hydroxy-2-fluoro-                                                     16-prostynoic acid                                         639    583          9-oxo-15-hydroxy-7a-homo-                                                      16-prostynoic acid                                         640    584          9-oxo-15-hydroxy-2-phenyl-                                                     16-prostynoic acid                                         641    589          9-oxo-15-hydroxy-3-methyl-                                                     16-prostynoic acid                                         642    590          9-oxo-15-hydroxy-3-thia-                                                       16-prostynoic acid                                         643    591          9-oxo-15-hydroxy-10a-homo-                                                     16-prostynoic acid                                         644    592          9-oxo-15-hydroxy-10a-homo-                                                     7-nor-16-prostynoic acid                                   645    593          9-oxo-15-hydroxy-7a,10a-                                                       bishomo-16-prostynoic acid                                 646    594          9-oxo-15-hydroxy-16-yne-5-                                                     cis-prostenoic acid                                        647    595          9-oxo-15-hydroxy-16-cis-                                                       prostenoic acid                                            648    596          9-oxo-hydroxy-6,7-dinor-                                                       16-cis-prostenoic acid                                     649    597          9-oxo-15-hydroxy-7a,7b-bis-                                                    homo-16-cis-prostenoic acid                                650    598          9-oxo-15-hydroxy-2-ethyl-                                                      16-cis-prostenoic acid                                     651    599          9-oxo-15-hydroxy-3,3-di-                                                       methyl-16-cis-prostenoic                                                       acid                                                       652    600          9-oxo-15-hydroxy-3-oxa-16-                                                     cis-prostenoic acid                                        653    601          9-oxo-15-hydroxy-7-nor-16-                                                     cis-prostenoic acid                                        654    602          9-oxo-15-hydroxy-2-fluoro-                                                     16-cis-prostenoic acid                                     655    603          9-oxo-15-hydroxy-7a-homo-                                                      16-cis-prostenoic acid                                     656    604          9-oxo-15-hydroxy-2-phenyl-                                                     16-cis-prostenoic acid                                     657    609          9-oxo-15-hydroxy-2-methyl-                                                     16-cis-prostenoic acid                                     658    610          9-oxo-15-hydroxy-3-thia-                                                       16-cis-prostenoic acid                                     659    611          9-oxo-15-hydroxy-10a-homo-                                                     16-cis-prostenoic acid                                     660    612          9-oxo-15-hydroxy-10a-homo-                                                     7-nor-16-cis-prostenoic                                                        acid                                                       661    613          9-oxo-15-hydroxy-7a,10a-                                                       bishomo-16-cis-prosten-                                                        oic acid                                                   662    614          9-oxo-15-hydroxy-5-cis-                                                        16-cis-prostadienoic                                                           acid                                                       ______________________________________                                    

EXAMPLE 663 Ethyl 9-oxo-15-hydroxy-16-trans-prostenoate

To a mixture of 1 g. of ethyl 9-oxo-15-hydroxy-16-prostynoate (Example 575), 11 ml. of water and 27 ml. of dimethylformamide is added 27 ml. of 0.45 N chromous sulfate solution. The mixture is stirred for 48 hours under nitrogen atmosphere. The mixture then is extracted with ether several times and the combined extracts are taken to dryness. Silica gel chromatography gives the subject product as an oil.

EXAMPLES 664 - 682

Treatment of the 9-oxo-15-hydroxy-16-prostynoates listed in Table 8A below with chromous sulfate in the manner of Example 663 is productive of the product 9-oxo-15-hydroxy-16-trans-prostenoates of the table.

                  TABLE 8A                                                         ______________________________________                                                Starting     Product                                                    Ex-    16-prostenoate                                                                              9-oxo-15-hydroxy-16-                                       ample  of Example   trans-prostenoate                                          ______________________________________                                         664    576          Ethyl 9-oxo-15-hydroxy-                                                        6,7-dinor-16-trans-                                                            prostenoate                                                665    577          Ethyl 9-oxo-15-hydroxy-                                                        7a,7b-bishomo-16-trans-                                                        prostenoate                                                666    578          Ethyl 9-oxo-15-hydroxy-                                                        2-ethyl-16-trans-pros-                                                         tenoate                                                    667    579          Ethyl 9-oxo-15-hydroxy-                                                        3,3-dimethyl-16-trans-                                                         prostenoate                                                668    580          Ethyl 9-oxo-15-hydroxy-                                                        3-oxa-16-trans-prosten-                                                        oate                                                       669    581          Ethyl 9-oxo-15-hydroxy-                                                        7-nor-16-trans-pros-                                                           tenoate                                                    670    582          Ethyl 9-oxo-15-hydroxy-                                                        2-fluoro-16-trans-pros-                                                        tenoate                                                    671    583          Ethyl 9-oxo-15-hydroxy-                                                        7a-homo-16-trans-pros-                                                         tenoate                                                    672    584          Ethyl 9-oxo-15-hydroxy-                                                        2-phenyl-16-trans-pros-                                                        tenoate                                                    673    585          Butyl 9-oxo-15-hydroxy-                                                        16-trans-prostenoate                                       674    586          Isopropyl 9-oxo-15-                                                            hydroxy-16-trans-pros-                                                         tenoate                                                    675    587          methyl 9-oxo-15-hydroxy-                                                       16-trans-prostenoate                                       676    588          Decyl 9-oxo-15-hydroxy-                                                        16-trans-prostenoate                                       677    589          Ethyl 9-oxo-15-hydroxy-                                                        2-methyl-16-trans-pros-                                                        tenoate                                                    678    590          Ethyl 9-oxo-15-hydroxy-                                                        3-thia-16-trans-pros-                                                          tenoate                                                    679    591          Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-16-trans-pros-                                                        tenoate                                                    680    592          Ethyl 9-oxo-15-hydroxy-                                                        10a-homo-7-nor-16-trans-                                                       prostenoate                                                681    593          Ethyl 9-oxo-15-hydroxy-                                                        7a,10a-bishomo-16-trans-                                                       prostenoate                                                682    594          Methyl 9-oxo-15-hydroxy-                                                       5-cis,16-trans-prosta-                                                         dienoate                                                   ______________________________________                                    

EXAMPLES 683-698

Saponification of the alkyl 9-oxo-15-hydroxy-16-trans-prostenoates listed in Table 8B below by the procedure described in Example 495 is productive of the corresponding prostenoic acids of the table.

                  TABLE 8B                                                         ______________________________________                                                Starting     Product 9-oxo-15-                                          Ex-    alkyl ester  hydroxy-16-trans                                           ample  of Example   prostenoic acids                                           ______________________________________                                         683    663          9-oxo-15-hydroxy-16-                                                           trans-prostenoic acid                                      684    664          9-oxo-15-hydroxy-6,7-                                                          dinor-16-trans-prosten-                                                        oic acid                                                   685    665          9-oxo-15-hydroxy-7a,7b-                                                        bishomo-16-trans-pros-                                                         tenoic acid                                                686    666          9-oxo-15-hydroxy-2-                                                            ethyl-16-trans-prosten-                                                        oic acid                                                   687    667          9-oxo-15-hydroxy-3,3-                                                          dimethyl-16-trans-pros-                                                        tenoic acid                                                688    668          9-oxo-15-hydroxy-3-oxa-                                                        16-trans-prostenoic acid                                   689    669          9-oxo-15-hydroxy-7-nor-                                                        16-trans-prostenoic acid                                   690    670          9-oxo-15-hydroxy-2-                                                            fluoro-16-trans-pros-                                                          tenoic acid                                                691    671          9-oxo-15-hydroxy-7a-                                                           homo-16-trans-prostenoic                                                       acid                                                       692    672          9-oxo-15-hydroxy-2-                                                            phenyl-16-trans-pros-                                                          tenoic acid                                                693    677          9-oxo-15-hydroxy-2-meth-                                                       yl-16-trans-prostenoic                                                         acid                                                       694    678          9-oxo-15-hydroxy-3-thia-                                                       16-trans-prostnoic acid                                    695    679          9-oxo-15-hydroxy-10a-                                                          homo-16-trans-prostenoic                                                       acid                                                       696    680          9-oxo-15-hydroxy-10a-                                                          homo-7-nor-16-trans-                                                           prostenoic acid                                            697    681          9-oxo-15-hdroxy-7a,10a-                                                        bishomo-16-trans-pro-                                                          stenoic acid                                               698    682          9-oxo-15-hydroxy-5-cis,                                                        16-trans-prostadienoic                                                         acid                                                       ______________________________________                                    

EXAMPLE 699 Preparation of 9-oxo-15-hydroxy-3,3-dimethylprostanoic acid

A 2 g. sample of 9-oxo-15-hydroxy-3,3-dimethyl-13-trans-prostenoic acid is hydrogenated using 700 mg. of 10% palladium on carbon in 50 ml. of absolute alcohol. The catalyst is removed by filtration and the mother liquor is taken to dryness to give 2 g. of subject compound as an oil.

EXAMPLE 723 Preparation of 1-chloro-trans-1-octen-3-one

To a slurry of 233.5 g. (1.75 moles) of aluminum chloride in 390 ml. of carbon tetrachloride, saturated with acetylene and cooled in an ice bath, is added over 20 minutes 201.9 g. (1.50 moles) of hexanoyl chloride. After the addition is complete, acetylene is bubbled into the mixture as rapidly as it is absorbed and for 1 hour after absorption becomes slow. The mixture is poured onto 1700 g. of ice and 720 ml. of saturated brine. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are washed with saturated brine, dried (Na₂ SO₄) and evaporated. The residual oil is combined with 10 g. of hydroquinone and distilled to yield a colorless oil, b.p. 51°-52° C. (0.10 torr).

EXAMPLE 724 Preparation of 1-iodo-trans-1-octen-3-one

A mixture of 54.5 g. (0.364 mole) of sodium iodide and 40 g. (0.249 mole) of 1-chloro-trans-1-octen 3-one (Example 723) in 360 ml. of acetone is stirred and refluxed for 24 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between water and ether. The organic phase is washed with dilute sodium bicarbonate solution, brine, dried (MgSO₄) and evaporated to an oil. This material is used directly without purification.

EXAMPLE 725 Preparation of 1-bromo-trans-1-octen-3-one

A mixture of 68.0 g. (0.424 mole) of 1-chloro-trans-1-octen-3 one (Example 723) and 444 g. (4.24 moles) of anhydrous lithium bromide in 900 ml. of 2-pentanone is refluxed for 30 minutes, cooled, and partitioned between ice water and ether. The organic phase is washed with water and saturated brine, dried (NaSO₄), and evaporated to an oil. This material is used directly without purification.

EXAMPLE 726 Preparation of 1-bromo-trans-1-octen-3-ol

To an ice cooled mixture of 14.29 g. (0.378 mole) of sodium borohydride in 400 ml. of anhydrous ethanol is added the crude 1-bromo-trans-1-octen-3-one (Example 725), from 0.424 mole of 1-chloro-trans-1-octen-3-one) over 30 minutes. The mixture is stirred for 2 hours with ice cooling and is then partitioned between ice water and benzene. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to an oil. Fractional distillation yields the title compound as a colorless oil, b.p. 66°-68° C. (0.025 torr).

EXAMPLE 727 Preparation of 1-chloro-trans-1-octen-3-ol

Treatment of 1-chloro-trans-1-octen-3-one (Example 723) with sodium borohydride in the manner of Example 726 is productive of the subject compound.

EXAMPLE 728 Preparation of 1-bromo-3-triphenylmethoxy-trans-1-octene

A mixture of 6.212 g. (0.030 mole) of 1-bromo-trans-1-octen-3-ol (Example 726) and 10.67 g. (0.033 mole) of triphenylmethyl bromide in 40 ml. of pyridine is heated to 100° C. for 1.5 hours under an inert atmosphere. The mixture is cooled and filtered. The filtrate is partitioned between ice water and ether. The organic phase is washed with cold dilute hydrochloric acid, saturated sodium bicarbonate solution, and saturated brine, dried (NaSO₄), and evaporated to an oil. The latter is dissolved in hexane and passed through 250 g. of Florisil ® to yield after evaporation a colorless oil. Found for C₂₇ H₂₉ OBr: C, 72.13; H, 6.61; Br, 17.57.

EXAMPLE 729 Preparation of 1-iodo-trans-1-octen-3-ol

Treatment of 63 g. (0.25 mole) of 1-iodo-trans-1-octen-3-one (Example 724) with sodium borohydride in the manner described in Example 726 gave 58 g. of yellow oil. The oil is purified by adsorption chromatography on a magnesia silica gel column using benzene as eluent to give a light yellow oil.

EXAMPLE 730 Preparation of 1-iodo-3-triphenylmethoxy-trans-1-octene

Treatment of 7.62 g. (0.03 mole) of 1-iodo-trans-1-octen-3-ol with 10.67 g. (0.033 mole) of triphenylmethyl bromide in pyridine in the manner described in Example 728 gave 13.448 g. (90%) of a colorless oil.

EXAMPLE 731 Preparation of 1-chloro-3-triphenylmethoxy-trans-1-octene

Treatment of 1-chloro-trans-1-octen-3-ol (Example 727) with triphenylmethyl chloride by the method described in Example 728 except that the heating period is extended to six hours provides the subject compound.

EXAMPLE 732 Preparation of 11-deoxy-prostaglandin-E₁ methyl ester and methyl 15-hydroxy-9-oxo-13-cis-prostenoate

To a slurry of 0.535 g. (0.022 g. atom) of magnesium in 6 ml. of tetrahydrofuran is added under an inert atmosphere 2 ml. of a solution of 6.548 g. (0.01455 mole) of 1-bromo-3-trityloxy-trans-1-octene (Example 728) in 8 ml. of tetrahydrofuran. Reaction is initiated by warming the mixture to 45° C. and adding 1 drop of methyl iodide. The remainder of the halide is added at a rate to maintain a temperature of 43°-46° C. and the mixture is heated at 45° C. for 1 hour after complete addition of the halide. The Grignard reagent is cooled and added to an ice cooled solution of 2.615 g. (0.0117 mole) of 2-(6-carbomethoxyhexyl) 2-cyclopentenone (Example 83) and 0.229 g. of Copper (I) iodide-tri-in-butylphosphine in 6 ml. of ether over 6 minutes. The mixture is stirred with ice cooling for 30 minutes and poured into 200 ml. of saturated ammonium chloride. The mixture is extracted into ether and the organic phase is washed with water and saturated brine, dried (NaSO₄) and evaporated. The residual oil is heated to 80° C. for 30 minutes with 80% aqueous acetic acid under an inert atmosphere. This mixture is cooled, evaporated to dryness, and the residue is separated by dry column chromatography on silica gel using benzene-ethyl acetate 4:1 as eluent. The title compounds are isolated as oils with Δ 13 trans/Δ 13 cis in ratio of 10:1. Complete resolution is effected with partition chromatography [for a description see M. J. Weiss et al., Tetrahedron, 20, 357 (1964)] on acid-washed Celite -545 using heptane: acetonitrile (Hold Back Volume-1000 ml); 11-deoxy-prostaglandin-E₁ methyl ester is obtained in Hold Back Volume 3-5 and methyl 15-hydroxy-9-oxo-13-cis-prostenoate is obtained in Hold Back Volume 6-8.

EXAMPLE 733 Preparation of 11-deoxy-prostaglandin-E₁ methyl ester and methyl 15-hydroxy-9-oxo-13-cis-prostenoate

To a slurry of 0.243 g. (0.010 g. atom) of magnesium in 4 ml. of tetrahydrofuran is added under an inert atomsphere 2 ml. of a solution of 4.494 g. (0.010 mole) of 1-bromo-3-trityloxy-trans-1-octene in 4 ml. of tetrahydrofuran. Reaction is initiated by warming the mixture to 65° C and adding 1 drop of methyl iodide. The remainder of the halide is added at a rate to maintain a temperature of 65°-70° C. and the mixture is heated at 75°-80° C. for 30 minutes after complete addition of the halide. The Grignard reagent is cooled and added to 2.243 g. (0.010 mole) of 2-(6-carbomethoxyhexyl)-2-cyclopentenone and 0.200 g. of copper (I) iodide-tri-n-butylphosphine in 6 ml. of ether and worked up with saturated ammonium chloride solution and aqueous acetic acid in the manner of Example 121. The products are isolated as described in Example 732 to yield 11-deoxy-prostaglandin E₁ methyl ester and methyl 15-hydroxy-9-oxo-13-cis-prostenoate in a ratio of 2:1.

EXAMPLE 734 Preparation of 15-hydroxy-9-oxo-13-cis-prostenoic acid

Methyl 15-hydroxy-9-oxo-13-cis-prostenoic acid is treated with potassium hydroxide in aqueous methanol and worked up as described in Example 495 to yield the title compound, m.p. 71°-75° C.

EXAMPLE 735 Preparation of Prostaglandin-E₁ and 9-oxo-qb 11α,15-dihydroxy-13-cis-prostenoic acid

A Grignard reagent is prepared as described in Example 732 from 0.535 g. (0.022 g. atom) of magnesium, 6.742 g. (0.015 mole) of 1-bromo-3-triphenylmethoxy-trans-1-octene (Example 728), and 11 ml. of tetrahydrofuran at a temperature of 40°-42° C. The Grignard reagent is added to 3.95 g. of 2-(6-carbotetrahydropyranyloxyhexyl)-4-tetrahydropyranyloxy-2-cyclopentenone (Example 95) and 0.589 g. of copper (I) iodide tri-n-butylphosphine in 10 ml. of tetrahydrofuran and is worked up with ammonium chloride as described in Example 732. The protecting groups are removed by treating the worked up material, as described in Example 121, with 320 mol of acetic acid-water-tetrahydrofuran 2:1:1 at 45° C. and the products are isolated by chromatography on silica gel with a benzene-ethyl acetate gradient and resolved via partition chromatography on acid-washed Celite 545.

EXAMPLE 736 Preparation of Prostaglandin-E₁, and 9-oxo-11α,15-dihydroxy-13-cis-prostenoic acid

Treatment of 2-(6-carbotetrahydropyranylhexyl)-4-tetrahydropyranyloxy-2-cyclopentenone (Example 95) with the Grignard reagent prepared from 1-bromo-3-triphenylmethoxy-trans-1-octene (Example 728) in the presence of Copper (I) iodide tri-n-butylphosphine complex by the procedure described in Example 733 is productive of the subject compounds.

EXAMPLE 737 Preparation of 9α,15-dihydroxy-13-trans-prostenoic acid

To a solution of 433 mg. of 9-oxo-15-hydroxy-13-trans-prostenoic acid in 4.5 ml. of tetrahydrofuran, stirred in an ice bath under nitrogen atmosphere, is added dropwise 3.7 ml. of 0.76M lithium perhydro-9b-boraphenalylhydride. After 40 minutes at 0° C. there is added 1.62 ml. of 3N sodium hydroxide followed by 1.62 ml. of 30% hydrogen peroxide. Ether is added and the resulting solution is acidified with 2N hydrochloric acid. The ether layer is washed several times with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give the subject product as an oil.

EXAMPLES 738-893

Treatment of the 9-oxo derivatives designated in the table below with lithium perhydro-9b-boraphenalyl hydride by the procedure described in Example 737 provides the 9α,15-dihydroxy derivatives of the table.

                  TABLE 9                                                          ______________________________________                                                Starting 9-oxo-                                                         Ex-    derivative of Product 9α,15-Dihydroxy                             ample  Example       Derivative                                                ______________________________________                                         738    375           9α,15-dihydroxy-5,6,7-                                                   trinor-13-trans-prosten-                                                       oic acid                                                  739    376           9α,15-dihydroxy-7a,7b-                                                   bishomo-13-trans-pros-                                                         tenoic acid                                               740    377           9α,15-dihydroxy-2-ethyl-                                                 13-trans-prostenoic                                                            acid                                                      741    378           9α,15-dihydroxy-3,3-di-                                                  methyl-13-trans-prosten-                                                       oic acid                                                  742    379           9α,15-dihydroxy-3-oxa-                                                   13-trans-prostenoic                                                            acid                                                      743    380           9α,15-dihydroxy-7-nor-                                                   13-trans-prostenoic acid                                                       acid                                                      744    381           9α,15-dihydroxy-2-fluoro-                                                13-trans-prostenoic acid                                  745    382           9α,-15-dihydroxy-7a-homo-                                                13-trans-prostenoic acid                                  746    383           9α,15-dihydroxy-2-phenyl-                                                13-trans-prostenoic acid                                  747    384           9α,15-dihydroxy-2-methyl-                                                13-trans-prostenoic acid                                  748    385           9α,15-dihydroxy-10a-homo-                                                13-trans-prostenoic acid                                  749    386           9α,15-dihydroxy-10a-homo-                                                5,6,7-trinor-13-trans-                                                         prostenoic acid                                           750    387           9α,15-dihydroxy-10a-homo-                                                7-nor-13-trans-prosten-                                                        oic acid                                                  751    388           9α,15-dihydroxy-7a,10a-                                                  bishomo-13-trans-pros-                                                         tenoic acid                                               752    389           9α,15-dihydroxy-3-thia-                                                  13-trans-prostenoic                                                            acid                                                      753    390           9α,15-dihydroxy-13-trans-                                                prostenoic acid                                           754    391           9α,15-dihydroxy-13-trans-                                                prostenoic acid                                           755    392           9α,15-dihydroxy-13-trans-                                                prostenoic acid                                           756    393           9α,15-dihydroxy-13-trans-                                                prostenoic acid                                           757    394           9α,15-dihydroxy-5-cis,13-                                                trans-prostadienoic acid                                  758    395           9α,14-dihydroxy-20-nor-                                                  13-trans-prostenoic acid                                  759    396           9α,15-dihydroxy-20-meth-                                                 yl-13-trans-prostenoic                                                         acid                                                      760    397           9α,15-dihydroxy-16-ethyl-                                                13-trans-prostenoic acid                                  761    398           9α,15-dihydroxy-16-meth-                                                 yl-20-nor-13-trans-pros-                                                       tenoic acid                                               762    399           9α,15-dihydroxy-19-meth-                                                 yl-13-trans,18-prosta-                                                         dienoic acid                                              763    400           9α,15-dihydroxy-18,19-di-                                                methyl-13-trans,18-pros-                                                       tadienoic acid                                            764    401           9α,145-dihydroxy-13-trans,                                               17-cis-prostadienoic acid                                 765    402           9α,15-dihydroxy-5,6,7-                                                   trinor-13-trans,17-cis-                                                        prostadienoic acid                                        766    403           9α,15-dihydroxy-6,7-di-                                                  nor-13-trans,17-cis-                                                           prostadienoic cid                                         767    404           9α,15-dihydroxy-7a,7b-                                                   bishomo-13-trans,17-                                                           cis-prostandienoic acid                                   768    405           9α,15-dihydroxy-2-ethyl-                                                 13-trans,17-cis-pros-                                                          tadienoic acid                                            769    406           9α,15-dihydroxy-3,3-di-                                                  methyl-13-trans,17-cis-                                                        prostadienoic acid                                        770    407           9α,15-dihydroxy-3-oxa-                                                   13-trans,17-cis-pros-                                                          tadienoic acid                                            771    408           9α,15-dihydroxy-7-nor-                                                   13-trans,17-cis-pros-                                                          tadienoic acid                                            772    409           9α,15-dihydroxy-2-fluoro-                                                13-trans,17-cis-pros-                                                          tadienoic acid                                            773    410           9α,15-dihydroxy-7a-homo-                                                 13-trans,17-cis-pros-                                                          tadienoic acid                                            774    411           9α,15-dihydroxy-2-phen-                                                  yl-13-trans,17-cis-                                                            prostadienoic acid                                        775    412           9α,15-dihydroxy-2-meth-                                                  yl-13-trans,17-cis-                                                            prostadienoic acid                                        776    413           9α,15-dihydroxy-10a-ho-                                                  mo-13-trans,17-cis-                                                            prostadienoic acid                                        777    414           9α,15-dihydroxy-10a-ho-                                                  mo-5,6,7-trinor-13-                                                            trans,17-cis-prostadi-                                                         enoic acid                                                778    415           9α,15-dihydroxy-10a-ho-                                                  mo-7-nor-13-trans,17-                                                          cis-prostadienoic acid                                    779    416           9α,15-dihydroxy-7a,10a-                                                  bishomo-13-trans,17-                                                           cis-prostadienoic acid                                    780    417           9α,15-dihydroxy-3-thia-                                                  13-trans,17-cis-pros-                                                          tadienoic acid                                            781    418           9α,15-dihydroxy-13-                                                      trans,7-cis-prostadi-                                                          enoic acid                                                782    419           9α,15-dihydroxy-13-                                                      trans,17-cis-prostadi-                                                         enoic acid                                                783    420           9α,15-dihydroxy-13-                                                      trans,17-cis-prostadi-                                                         enoic acid                                                784    421           9α,15-dihydroxy-13-trans,                                                17-cis-prostadienoic acid                                 785    422           9α,15-dihydroxy-5,6,7-                                                   trinor-19-isobutyl-13-                                                         trans,18-prostadien-                                                           oic acid                                                  786    423           9α,15-dihydroxy-5,6,7-                                                   19,20-pentanor-13-trans,                                                       17-prostadienoc acid                                      787    424           9α,15-dihydroxy-19,20-di-                                                nor-13-trans,18-prosta-                                                        dienoic acid                                              788    425           9α,15-dihydroxy-17,20-di-                                                methyl-20-isopropenyl-13-                                                      trans-prostenoic acid                                     789    426           9α,15-dihydroxy-16-ethyl-                                                6,7,19,20-tetranor-13-                                                         trans-prostenoic acid                                     790    427           9α,15-dihydroxy-18,19-                                                   dimethyl-6,7-dinor-13-                                                         trans,18-prostadienoic                                                         acid                                                      791    428           9α,15-dihydroxy-16-ethyl-                                                7a,7b-bishomo-13-trans-                                                        prostenoic acid                                           792    429           9α,15-dihydroxy-19-meth-                                                 yl-7a,7b-bishomo-13-                                                           trans,18-prostadienoic                                                         acid                                                      793    430           9α,15-dihydroxy-2-ethyl-                                                 19,20-dinor-13-trans-                                                          prostenoic acid                                           794    431           9α,15-dihydroxy-2,20-di-                                                 ethyl-13-trans-prosten-                                                        oic acid                                                  795    432           9α,15-dihydroxy-2-ethyl-                                                 16-methyl-20-nor-13-                                                           trans-prostenoic acid                                     796    433           9α,15-dihydroxy-2-ethyl-                                                 18,19-dimethyl-13-                                                             trans,18-prostadienoic                                                         acid                                                      797    434           9α,15-dihydroxy-3,3-di-                                                  methyl-18,19,20-trinor-                                                        13-trans-prostenoic                                                            acid                                                      798    435           9α,165-dihydroxy-3,3,20-                                                 trimethyl-13-trans-                                                            prostenoic acid                                           799    436           9α,15-dihydroxy-3,3,16-                                                  trimethyl-20-nor-13-                                                           trans-prostenoic acid                                     800    437           9α,15-dihydroxy-3,3-di-                                                  methyl-19-isobutyl-13-                                                         trans,18-prostadienoic                                                         acid                                                      801    438           9α,15-dihydroxy-3,3-di-                                                  methyl-19,20-dinor-13-                                                         trans,17-prostadienoic                                                         acid                                                      802    439           9α,15-dihydroxy-3-oxa-20-                                                nor-13-trans-prostenoic                                                        acid                                                      803    440           9α,15-dihydroxy-3-oxa-20-                                                methyl-13-trans-prosten-                                                       oic acid                                                  804    441           9α,15-dihydroxy-3-oxa-16-                                                ethyl-13-trans-prosten-                                                        oic acid                                                  805    442           9α,15-dihydroxy-3-oxa-16-                                                methyl-20-nor-13-trans-                                                        prostenoic acid                                           806    443           9α,15-dihydroxy-3-oxa-                                                   19,20-dinor-13-trans,17-                                                       prostadienoic acid                                        807    444           9α,15-dihydroxy-7,19,20-                                                 trinor-13-trans,17-                                                            prostadienoic acid                                        808    445           9α,15-dihydroxy-7-nor-                                                   18,19-dimethyl-13-trans,                                                       18,prostadienoic acid                                     809    446           9α,15-dihydroxy-7,18,19,-                                                20-tetranor-16-methyl-13-                                                      trans-prostenoic acid                                     810    447           9α,15-dihydroxy-2-fluoro-                                                20-nor-13-trans-prosten-                                                       oic acid                                                  811    448           9α,15-dihydroxy-2-fluoro-                                                20-ethyl-13-trans-pros-                                                        tenoic acid                                               812    449           99α,15-dihydroxy-2-fluoro-                                               16-ethyl-19,20-dinor-13-                                                       trans-prostenoic acid                                     813    450           9α,15-dihydroxy-2-fluoro-                                                16-methyl-20-nor-13-                                                           trans-prostenoic acid                                     814    451           9α,15-dihydroxy-2-fluoro-                                                19-methyl-13-trans,18-                                                         prostdienoic acid                                         815    452           9α,15-dihydroxy-7a-homo-                                                 18,19-dimethyl-13-trans,                                                       18-prostadienoic acid                                     816    453           9α,15-dihydroxy-7a-homo-                                                 19,20-dinor-13-trans,                                                          17-prostadienoic acid                                     817    454           9α,15-dihydroxy-2-phenyl-                                                20-nor-13-trans-prosten-                                                       oic acid                                                  818    455           9α,15-dihydroxy-2-phenyl-                                                20-ethyl-13-trans-pros-                                                        tenoic acid                                               819    456           9α,15-dihydroxy-2-phenyl-                                                16-ethyl-13-trans-pros-                                                        tenoic acid                                               820    484           9α,15-dihydroxy-20-nor-5-                                                cis,13-trans-prostadi-                                                         enoic acid                                                821    485           9α,15-dihydroxy-20-meth-                                                 yl-5-cis,13-trans-pros-                                                        tadienoic acid                                            822    486           9α,15-dihydroxy-16-ethyl-                                                5-cis,13-trans-prosta-                                                         dienoic acid                                              823    487           9α,15-dihydroxy-16-meth-                                                 yl-20-nor-5-cis,13-                                                            trans-prostadienoic                                                            acid                                                      824    488           9α,14-dihydroxy-19-meth-                                                 yl-5-cis,13-trans,18-                                                          prostatrienoic acid                                       825    489           9α,15-dihydroxy-18,19-                                                   dimethyl-5-cis,13-                                                             trans,18-prostatrien-                                                          oic acid                                                  826    490           9α,15-dihydroxy-19,20-di-                                                nor-5-cis,13-trans,17-                                                         prostatrienoic acid                                       827    491           9α,15-dihydroxy-5-cis,-                                                  13-trans,17-cis-prosta-                                                        trienoic acid                                             828    734           9α,15-dihydroxy-13-cis-                                                  prostenoic acid                                           829    735           9α,11α,15-trihydroxy-13-                                           cis-prostenoic acid                                       830    615           9α,15-dihydroxy-2-ethyl-                                                 prostanoic acid                                           831    616           9α,15-dihydroxy-3,3-di-                                                  methyl-prostanoic acid                                    832    617           9α,15-dihydroxy-3-oxa-                                                   prostanoic acid                                           833    618           9α,15-dihydroxy-2-fluoro-                                                prostanoic acid                                           834    619           9α,15-dihydroxy-2-phenyl-                                                prostanoic acid                                           835    620           9α,15-dihydroxy-2-meth-                                                  yl-prostanoic acid                                        836    621           9α,15-dihydroxy-3-thia-                                                  prostanoic acid                                           837    622           9α,15-dihydroxy-5-cis-                                                   prostenoic acid                                           838    623           9α,15-dihydroxy-2-ethyl-                                                 19,20-dinor-prostanoic                                                         acid                                                      839    624           9α,15-dihydroxy-3,3-di-                                                  methyl-19,20-dinor-pros-                                                       tanoic acid                                               840    625           9α,15-dihydroxy-3-oxa-                                                   19,20-dinor-prostanoic                                                         acid                                                      841    626           9α,15-dihydroxy-2-fluoro-                                                19,20-dinor-prostanoic                                                         acid                                                      842    627           9α,15-dihydroxy-2-phenyl-                                                19,20-dinor-prostanoic                                                         acid                                                      843    628           9α,15-dihydroxy-2-meth-                                                  yl-19,20-dinor-prostan-                                                        oic acid                                                  844    629           9α,15-dihydroxy-3-thia-                                                  19,20-dinor-prostanoic                                                         acid                                                      845    630           9α,15-dihydroxy-19,20-di-                                                nor-5-cis-prostenoic acid                                 846    631           9α,15-dihydroxy-16-pros-                                                 tynoic acid                                               847    632           9α,15-dihydroxy-6,7-di-                                                  nor-16-prostynoic acid                                    848    633           9α,15-dihydroxy-7a,7b-                                                   bishomo-16-prostynoic                                                          acid                                                      849    634           9α,15-dihydroxy-2-ethyl-                                                 16-prostynoic acid                                        850    635           9α,15-dihydroxy-3,3-di-                                                  methyl-16-prostynoic                                                           acid                                                      851    636           9α,15-dihydroxy-3-oxa-16-                                                prostynoic acid                                           852    637           9α,15-dihydroxy-7-nor-16-                                                prostynoic acid                                           853    638           9α,15-dihydroxy-2-fluoro-                                                16-prostynoic acid                                        854    639           9α,15-dihydroxy-7a-homo-                                                 16-prostynoic acid                                        855    640           9α,15-dihydroxy-2-phenyl-                                                16-prostynoic acid                                        856    641           9α,15-dihydroxy-2-methyl-                                                16-prostynoic acid                                        857    642           9α,15-dihydroxy-3-thia-                                                  16-prostynoic acid                                        858    643           9α,15-dihydroxy-10a-ho-                                                  mo-16-prostynoic acid                                     859    644           9α,15-dihydroxy-10a-ho-                                                  mo-7-nor-17-prostynoic                                                         acid                                                      860    645           9α,15-dihydroxy-7a,10a-                                                  bishomo-16-prostynoic                                                          acid                                                      861    646           9α,15-dihydroxy-16-yne-                                                  5-cis-prostenoic acid                                     862    683           9α,15-dihydroxy-16-trans-                                                prostenoic acid                                           863    684           9α,15-dihydroxy-6,7-di-                                                  nor-16-trans-prostenoic                                                        acid                                                      864    685           9α,15-dihydroxy-7a,7b-                                                   bishomo-16-trans-pros-                                                         tenoic acid                                               865    686           9α,15-dihydroxy-2-ethyl-                                                 16-trans-prostenoic acid                                  866    687           9α,15-dihydroxy-3,3-di-                                                  methyl-16-trans-prosten-                                                       oic acid                                                  867    688           9α,15-dihydroxy-3-oxa-16-                                                trans-prostenoic acid                                     868    689           9α,15-dihydroxy-7-nor-16-                                                trans-prostenoic acid                                     869    690           9α,15-dihydroxy-2-fluoro-                                                16-trans-prostenoic acid                                  870    691           9α,15-dihydroxy-7a-homo-                                                 16-trans-prostenoic acid                                  871    692           9α,15-dihydroxy-2-phenyl-                                                16-trans-prostenoic acid                                  872    693           9α,15-dihydroxy-2-methyl-                                                16-trans-prostenoic acid                                  873    694           9α,15-dihydroxy-3-thia-                                                  16-trans-prostenoic acid                                  874    695           9α,15-dihydroxy-10a-homo-                                                16-trans-prostenoic acid                                  875    696           9α,15-dihydroxy-10a-homo-                                                7-nor-16-trans-prosten-                                                        oic acid                                                  876    697           9α,15-dihydroxy-7a,10a-                                                  bishomo-16-trans-pros-                                                         tenoic acid                                               877    698           9α,15-dihydroxy-5-cis,-                                                  16-trans-prostadienoic                                                         acid                                                      878    647           9α,15-dihydroxy-16-cis-                                                  prostenoic acid                                           879    648           9α,15-dihydroxy-6,7-di-                                                  nor-16-cis-prostnoic                                                           acid                                                      880    649           9α,15-dihydroxy-7a,7b-                                                   bishomo-16-cis-prosten-                                                        oic acid                                                  881    650           9α,15-dihydroxy-2-ethyl-                                                 16-cis-prostenoic acid                                    882    651           9α,15-dihydroxy-3,3-di-                                                  methyl-16-cis-prosten-                                                         oic acid                                                  883    652           9α,15-dihydroxy-3-oxa-                                                   16-cis-prostenoic acid                                    884    653           9α,15-dihydroxy-7-nor-                                                   16-cis-prostenoic acid                                    885    654           9α,15-dihydroxy-2-fluoro-                                                16-cis-prostenoic acid                                    886    655           9α,15-dihydroxy-7a-homo-                                                 16-cis-prostenoic acid                                    887    656           9α,15-dihydroxy-2-phenyl-                                                16-cis-prostenoic acid                                    888    657           9α,15-dihydroxy-2-methyl-                                                16-cis-prostenoic acid                                    889    658           9α,15-dihydroxy-3-thia-                                                  16-cis-prostenoic acid                                    890    659           9α,15-dihydroxy-10a-ho-                                                  mo-16-cis-prostenoic                                                           acid                                                      891    660           9α,15-dihydroxy-10a-ho-                                                  mo-7-nor-16-cis-prosten-                                                       oic acid                                                  892    661           9α,15-dihydroxy-7a,10a-                                                  bishomo-16-cis-prosten-                                                        oic acid                                                  893    662           9α,15-dihydroxy-5-cis-                                                   16-cis-prostadienoic                                                           acid                                                      ______________________________________                                    

EXAMPLE 894 Preparation of 2-carbalkoxy (methyl/ethyl)-2-(2-methoxyethyl)-cyclopentan-1-one

Treatment of 2-cyclopentanone carboxylate (mixed methyl and ethyl esters) with 2-methoxyethyl bromide by the method of Example 1 furnishes the subject compound as an oil, b.p. 90° C. (0.1 mm).

EXAMPLE 895 Preparation of 2-(2-methoxyethyl)cyclopentan-1-one

Heating 8 g. of 2-carboalkoxy (methyl/ethyl)-2-(2-methoxyethyl)-cyclopentan-1-one (Example 894) in 8 ml. of 20% aqueous hydrochloric acid at reflux for 3.5 hours and isolating the product by the method of Example 2 furnishes the subject compound as an oil, b.p. 45°-50° C. (0.02 mm).

EXAMPLE 896 Preparation of 1-acetoxy-2-(2-methoxyethyl)cyclopent-1-ene

The subject compound is prepared from 2-(2-methoxyethyl)cyclopentan-1-one (Example 895) and acetic anhydride by the procedure of Example 10. The product is an oil, b.p. 60° C (0.2 mm.)

EXAMPLE 897 Preparation of 2-(2-hydroxyethyl)-cyclopent-2-en-1one

The enol acetate of Example 898 is brominated and dehydrobrominated by the method described in Example 13. The crude product is then dissolved in methylene chloride and is added a7 -78° C. to a methylene chloride solution containing about seven molar equivalents of boron tribromide. After 1 hour at -78° C. the solution is allowed to warm to room temperature and is then kept at ambient temperatures for a total of 18 hours. The mixture is poured into water and extracted with ether. The organic phase is washed with saturated saline solution, then water and is dried. Evaporation of solvents leaves subject product, which is purified by distillation. The combined organic phases are washed with ice cold 5% sodium hydroxide solution, ice cold 5% hydrochloric acid, and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives a pale yellow oil; λ max 5.85 μ (carbonyl group).

EXAMPLE 898 Preparation of 2-formylmethylcycopent-2-en-1-one

Chromium trioxide (0.6 mol) is added to a stirring solution of (1.2 mol) of anhydrous pyridine in 1500 ml. of anhydrous methylene chloride cooled in an ice bath. The deep red suspension is stirred for 15 minutes at 0° C. and 45 minutes at ambient temperature. A solution of 01.5 mol of 2-(2-hydroxyethyl)-cyclopent-2-en-1-one (Example 897) in 50 ml. of methylene chloride is added, all at once, to the suspension. A black terry deposit is formed immediately. After stirring the mixture for 25 minutes at ambient temperature, the methylene chloride is decanted from the tarry precipitate which is then triturated several times with ether.

EXAMPLE 899 Preparation of 2-(6-carboxy-2-cis-hexenyl)-cyclopent-2-en-1-one

a mixture of 0.194 g. (0.007952 mole) of sodium hydride (free of mineral oil) and 5.5 ml. of dimethylsulfoxide is heated to 70° C. until gas evolution ceases under a nitrogen atmosphere. The resulting solution is cooled below room temperature and treated with a solution of 1,400 g. (0.00316 mole) of 4-carboxybutyltriphenyl phosphonium bromide [E. J. Corey et al., J. Am. Chem. Soc., 91, 5675 (1969)] in 6 ml. of dimethylsulfoxide. To the resulting red solution is added 0.00263 mole of 2-formylmethylcyclopent-2-en-1-one (Example 898) in 2 ml. of dimethylsulfoxide and the mixture is stirred at room temperature for 2.25 hours. The mixture is poured into ice water, sodium hydroxide solution is added to pH 12, and the neutral materials are extracted with diethyl ether. The basic phase is acidified with dilute hydrochloric acid and is extracted with diethyl ether. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to a semicrystalline mass. The latter is triturated with hot hexane, the solids are filtered off, and the filtrate is evaporated to yield the subject product as an oil.

EXAMPLE 900 Preparation of 2-(6-carbomethoxy-2-cis-hexenyl)-cyclopent-2-en-1-one

Treatment of 2-(6-carboxy-2-cis-hexenyl)-cyclopent-2-en-1-one (Example 899) with diazomethane in the usual manner is productive of the subject ester.

EXAMPLES 901-909

Hydrogenation of 13-trans-prostenoic acids designated in the table below by the procedure of Example 699 is productive of the prostanoic acids of the table.

                  TABLE 10                                                         ______________________________________                                                     Starting 13-                                                                   trans-pro-   Product                                               Ex-         stenoic acid Prostanoic                                            ample       of Example   Acid                                                  ______________________________________                                         901         397          9-oxo-15-hydroxy-                                                              16-ethyl-pro-                                                                  stanoic acid                                          902         398          9-oxo-15-hydroxy-                                                              16-methyl-20-                                                                  nor-prostanoic                                                                 acid                                                  903         400          9-oxo-15-hydroxy-                                                              18,19-dimethyl-                                                                prostanoic acid                                       904         426          9-oxo-15-hydroxy-                                                              16-ethyl-6,7,19,                                                               20-tetranor-pro-                                                               stanoic acid                                          905         428          9-oxo-15-hydroxy-                                                              16-ethyl-7a,7b-                                                                bishomo-prostan-                                                               oic acid                                              906         429          9-oxo-15-hydroxy-                                                              19-methyl-7a,7b-                                                               bishomo-prostan-                                                               oic acid                                              907         433          9-oxo-15-hydroxy-                                                              2-ethyl-18,19-                                                                 dimethyl-pro-                                                                  stanoic acid                                          908         436          9-oxo-15-hydroxy-                                                              3,3,16-trimethyl-                                                              20-nor-prostanoic                                                              acid                                                  909         476          9-oxo-15-hydroxy-                                                              7a,10a-bishomo-16-                                                             methyl-20-nor-                                                                 prostanoic acid                                       ______________________________________                                    

EXAMPLES 910-915

Treatment of the 9-oxo-alkyl esters designated in the table below with sodium borohydride by the procedure described in Example 257 is productive of the corresponding 9-hydroxy derivative of the table. These products are obtained as 9α- and 9β-hydroxy epimeric mixtures.

                  TABLE II                                                         ______________________________________                                                   Starting 9-oxo                                                       Ex-       derivative of                                                                               Product                                                 ample     Example      9α/9β-hydroxy derivative                     ______________________________________                                         910       260          ethyl 9α/9β,15-dihydroxy-                                           2-ethyl-13-trans-                                                              prostenoate                                             911       261          ethyl 9α/9β,15-dihydroxy-                                           3,3-dimethyl-13-trans-                                                         prostenoate                                             912       262          ethyl 9α/9β,15-dihydroxy-                                           3-oxa-13-trans-                                                                prostenoate                                             913       266          ethyl 9α/9β,15-dihydroxy-                                           2-phenyl-13-trans-                                                             prostenoate                                             914       272          ethyl 9α/9β,15-dihydroxy-                                           3-thia-13-trans-                                                               prostenoate                                             915       284          ethyl 9α/9β,15-dihydroxy-                                           13-trans,17-cis-                                                               prostadienoate                                          ______________________________________                                    

EXAMPLES 916-921

Saponification of the ethyl esters designated in the table below by the procedure described in Example 122 furnishes the carboxylic acids of the table.

                  TABLE 12                                                         ______________________________________                                                                  Product 9α/9β,15-di-                       Ex-       Starting ethyl hydroxy-13-trans-pro-                                 ample     ester of Example                                                                              stenoic acid                                          ______________________________________                                         916       910            9α/9β,15-dihydroxy-                                                 2-ethyl-13-trans-                                                              prostenoic acid                                       917       911            9α/9β,15-dihydroxy-                                                 3,3-dimethyl-13-                                                               trans-prostenoic                                                               acid                                                  918       912            9α/9β,15-dihydroxy-                                                 3-oxa-13-trans-                                                                prostenoic acid                                       919       913            9α/9β,15-dihydroxy-                                                 2-phenyl-13-trans-                                                             prostenoic acid                                       920       914            9α/9β,15-dihydroxy-                                                 3-thia-13-trans-                                                               prostenoic acid                                       921       915            9α/9β,15-dihydroxy-                                                 13-trans,17-cis-                                                               prostadienoic acid                                    ______________________________________                                    

EXAMPLES 922-932

Treatment of the cycloalkenones of Table 13, which follows, with the Grignard reagent, prepared from 1-bromo-3-triphenylmethoxy-trans-1-octene and magnesium according to the procedure of Example 733, hydrolyzing the intermediate 15-O-triphenylmethyl derivatives with glacial acetic acid-tetrahydrofura-water (4:2:1) according to the procedure of Example 121, and isolating the products in the manner described in Example 732 is productive of the product 9-oxo-15-hydroxy-13-cis-prostenoates and 9-oxo-15-hydroxy-13-trans-prostenoates of the table.

                                      TABLE 13                                     __________________________________________________________________________          Starting cyclopentenone                                                                    Product 15-hydroxy-13-cis-                                                                     Product 15-hydroxy-13-trans-                  Example                                                                             Ester of Example                                                                           prostenoate ester                                                                              prostenoate ester                             __________________________________________________________________________     922  23          ethyl 9-oxo-15-hydroxy-7a,7b-                                                                  ethyl 9-oxo-15-hydroxy-7a,7b-                                  bishomo-13-cis-prostenoate                                                                     bishomo-13-trans-prostenoate                  923  31          ethyl 9-oxo-15-hydroxy-2-ethyl-                                                                ethyl 9-oxo-15-hydroxy-2-                                      13-cis-prostenoate                                                                             ethyl-13-trans-prostenoate                    924  41          ethyl 9-oxo-15-hydroxy-3,3-di-                                                                 ethyl 9-oxo-15-hydroxy-3,3-di-                                 methyl-13-cis-prostenoate                                                                      methyl 13-trans-prostenoate                   925  46          ethyl 9-oxo-15-hydroxy-3-oxa-                                                                  ethyl 9-oxo-15-hydroxy-3-oxa-                                  13-cis-prostenoate                                                                             13-trans-prostenoate                          926  53          ethyl 9-oxo-15-hydroxy-7-nor-                                                                  ethyl 9-oxo-15-hydroxy-7-nor-                                  13-cis-prostenoate                                                                             13-trans-prostenoate                          927  70          ethyl 9-oxo-15-hydroxy-2-fluoro-                                                               ethyl 9-oxo-15-hydroxy-2-                                      13-cis-prostenoate                                                                             fluoro-13-trans-prostenoate                   928  84          n-decyl 9-oxo-15-hydroxy-                                                                      n-decyl 9-oxo-15-hydroxy-                                      13-cis-prostenoate                                                                             13-trans-prostenoate                          929  99          ethyl 9-oxo-15-hydroxy-2-methyl-                                                               ethyl 9-oxo-15-hydroxy-2-                                      13-cis-prostenoate                                                                             methyl-13-trans-prostenoate                   930  111         ethyl 9-oxo-15-hydroxy-10a-homo-                                                               ethyl 9-oxo-15-hydroxy-10a-                                    13-cis-prostenoate                                                                             homo-13-trans-prostenoate                     931  118         ethyl 9-oxo-15-hydroxy-3-thia-                                                                 ethyl 9-oxo-15-hydroxy-3-                                      13-cis-prostenoate                                                                             thia-13-trans-prostenoate                     932  900         methyl 9-oxo-15-hydroxy-5-                                                                     methyl 9-oxo-15-hydroxy-5-                                     cis, 13-cis-prostadienoate                                                                     cis, 13-trans-                                                                 prostadienoate                                __________________________________________________________________________

EXAMPLES 933-942

Saponification of the 13-cis-prostenoate alkyl esters designated in Table 14 below by the method described in Example 122 is productive of the 13-cis-prostenoic acids of the Table.

                  TABLE 14                                                         ______________________________________                                              Starting                                                                       13-cis-                                                                        prostenoate                                                                    Ester of                                                                  Ex.  Example   Product 13-cis-prostenoic acids                                 ______________________________________                                         933  922       9-oxo-15-hydroxy-7a,7b-bishomo-13-                                             cis-prostenoic acid                                             934  923       9-oxo-15-hydroxy-2-ethyl-13-cis-                                               prostenoic acid                                                 935  924       9-oxo-15-hydroxy-3,3-dimethyl-13-cis-                                          prostenoic acid                                                 936  925       9-oxo-15-hydroxy-3-oxa-13-cis-                                                 prostenoic acid                                                 937  926       9-oxo-15-hydroxy-7-nor-13-cis-                                                 prostenoic acid                                                 938  927       9-oxo-15-hydroxy-2-fluoro-13-cis-                                              prostenoic acid                                                 939  929       9-oxo-15-hydroxy-2-methyl-13-cis                                               prostenoic acid                                                 940  930       9-oxo-15-hydroxy-10a-homo-13-cis                                               prostenoic acid                                                 941  931       9-oxo-15-hydroxy-3-thia-13-cis-                                                prostenoic acid                                                 942  932       9-oxo-15-hydroxy-5-cis, 13-cis-                                                prostadienoic acid                                              ______________________________________                                    

EXAMPLES 943-954

Treatment of the 9-oxo-13-cis-prostenoic acids and esters of Table 15 below with lithium perhydro-9b-boraphenalyl hydride by the procedure described in Example 737 furnishes the 9α,15-dihydroxy-13-cis-prostenoic acids and esters of the table.

                  TABLE 15                                                         ______________________________________                                              Starting 9-                                                                    oxo-13-cis-                                                                    prostenoic                                                                     derivative                                                                               Product 9α,15-hydroxy-13-                                 Ex.  of Example                                                                               cis-prostenoic acid and esters                                  ______________________________________                                         943  933       9,15-dihydroxy-7a,7b-bishomo-                                                  13-cis-prostenoic acid                                          944  934       9,15-dihydroxy-2-ethyl-13-cis-                                                 prostenoic acid                                                 945  935       9,15-dihydroxy-3,3-dimethyl-13-cis-                                            prostenoic acid                                                 946  936       9,15-dihydroxy-3-oxa-13-cis-                                                   prostenoic acid                                                 947  937       9,15-dihydroxy-7-nor-13-cis-                                                   prostenoic acid                                                 948  938       9,15-dihydroxy-2-fluoro-13-cis-                                                prostenoic acid                                                 949  939       9,15-dihydroxy-2-methyl-13-cis-                                                prostenoic acid                                                 950  940       9,15-dihydroxy-10a-homo-13-cis-                                                prostenoic acid                                                 951  941       9,15-dihydroxy-3-thia-13-cis-                                                  prostenoic acid                                                 952  942       9,15-dihydroxy-5-cis,-13-cis-                                                  prostadienoic acid                                              953  932       methyl 9,15-dihydroxy-5-cis, -  13-cis-prostadienoate           954  928       n-decyl 9,15-dihydroxy-13-cis-                                                 prostenoate                                                     ______________________________________                                    

EXAMPLE 955 Preparation of 1-iodo-trans-1-octen-3-ol

A solution of 78.2 g. (0.310 moles) of 1-ioso-trans-1-octen-3-one (Example 724) in 150 ml. of absolute ethanol is added dropwise over 2 hours to a slurry of 6.49 g. (0.172 moles) of sodium borohydride in 50 ml. of absolute ethanol cooled in an ice bath. After the addition is complete, the mixture is stirred for 2 hours with ice cooling and is then poured into 1 l. of water. The mixture is extracted into benzene and the organic phase is washed with saturated brine, dried (Na₂ SO₄) and evaporated. The resulting oil is dissolved into 400 ml. of absolute ethanol and treated with 5 mole percent of p-carboxyphenylhydrazine at 70° C. for 1.5 hours to remove residual ketone. The mixture is cooled and evaporated and the residue is dissolved into 400 ml. of ether and is filtered. The filtrate is washed with dilute sodium bicarbonate solution and saturated brine, dried (Na₂ SO₄), and evaporated to an oil. This oil is chromatographyed upon 2 Kg. of Florisil® packed in hexane and the product is obtained upon elution with benzene Distillation of the product yields a colorless oil, b.p. 74°-76° C. (0.005 tor.).

EXAMPLE 956 Preparation of 1-iodo-3-(p-anisyldiphenylmethoxy)-trans-1-octene

A mixture of 14.92 g. (0.0588 mole) of 1-iodo-trans-1-octen-3-ol (Example 955) and 18.2 g. (0.0588 mole) of p-anisyldiphenylmethyl chloride in 165 ml. of dry pyridine is heated at 60° C. for 18 hours under an inert atmosphere. The mixture is cooled and the solvent is evaporated in vacuo. The residue is partitioned between ether and water, and the organic phase is washed with water and saturated brine, dried (MgSO₄), and evaporated. The residue is chromatographed upon 300 g. of Florisil ® packed in hexane and the product is eluted with hexane and 4:1 hexane-benzene the yield a colorless oil.

EXAMPLE 957 Preparation of methyl esters of dl-11-deoxyprostaglandin-E₁ and dl-11-deoxy-15-epi-prostaglandin E₁

To a solution of 6.030 g. (0.01215 mole) of 1-iodo-3-triphenylmethoxy-trans-1-octene (Example 730) in 8 ml. of toluene cooled to -78° C. under an inert atmosphere is added 5.2 ml. of a 2.34 M solution of n-butyllithium in hexane. The resulting solution is allowed to warm to -40° C. and is maintained at this temperature for 1 hour. To the solution containing 3-triphenylmethoxy-trans-1-octenyllithium is then added 5.0 ml. of a 2.44 M (0.0122 mole) solution of trimethylaluminum in heptane and the mixture is allowed to warm to -10° C. The mixture containing lithium trimethyl(3-triphenylmethoxy-trans-1-octenyl)alanate is then cooled to -78° C. and to it is added a solution of 2.725 g. (0.01215 mole) of 2-(6-carbomethoxyhexyl)-2-cyclopentenone (Example 83) dissolved in 10 ml. of diethyl ether. The mixture is allowed to warm to room temperature and is stirred at ambient temperature for 18 hours. The mixture is then poured onto ice and diluted hydrochloric acid and is extracted into ether. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to yield a colorless oil. This oil is heated with 100 ml. of 80% aqueous acetic acid at 80° C. for 1 hour under an inert atmosphere. The resulting mixture is cooled and evaporated in vacuo to dryness with 100 ml. of xylene to yield an oil. This oil is dry-column-chromatographed upon 400 g. of silica gel using 4:1 benzene-ethyl acetate as eluent to yield a total of 2.59 g. of dl-11-deoxyprostaglandin E₁ and dl-11-deoxy-15-epiprostaglandin E₁ methyl esters.

EXAMPLE 958 Preparation of 4-(trimethylsiloxy)-2-(6-carbotrimethylsiloxyhexyl)cyclopent-2-en-1-one

To a solution of 5 g. of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one (Example 94) in 10 ml. of dry N,N-dimethylformamide is added 5.4 g. of trimethylsilyl chloride in a nitrogen atmosphere. To the resulting solution cooled in a tap water bath is added 5.05 g. of triethylamine in 10 ml. of N,N-dimethylformamide dropwise. The resulting mixture is stirred at 60° C. in an oil-bath for 2 hours, then at ambient temperatures for 18 hours. Triethylamine hydrochloride is removed by filtration and the filtrate is taken to dryness. The residual oil is distilled to give 2.6 g. of product, b.p. 156°-157° C. (0.07 mm.).

EXAMPLE 958A Preparation of 4-(dimethylisopropylsiloxy)-2-(6-carbodimethylisopropylsiloxyhexyl)cyclopent-2-en-1-one

Treatment of 1 g. of 2-(6-carboxyhexyl)-4-hydroxy-cyclopent-2-en-1-one in 2 ml. of dry N,N-dimethylformamide containing 1.81 g. of dimethylisopropylsilyl chloride [E. J. C rey, R. K. Varma, J. Amer. Chem. Soc., 93, 7320 (1971)] 1.57 g. of triethylamine in 2 ml. of N,N-dimethylformamide in the manner described in Example 958 gives 1.45 g. of product after two evaporations with toluene.

EXAMPLE 959 Preparation of 4-(dimethyl-t-butylsiloxy)-2-(6-carbodimethyl-t-butylsiloxyhexyl)cyclopent-2-en-1-one

To a 0° C. solution of 2.0 gm. (8.55 mole) 4-hydroxy-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 94) and 3.65 gm. (54 mole) of imidazole in 5 ml. of dimethylformamide is added a slurry consisting of 4.07 gm. (27 mole) of dimethyl-t-butyl chlorosilane in 5 ml. of dimethylformamide. The slurry is rinsed in with an additional 1 ml. of dimethylformamide. The ice-bath is removed and the solution is stirred at 37° C. for four hours. The solution is then poured into 140 ml. of water and the aqueous solution is extracted twice with 70 ml. of isomeric hexanes. The organic layers are combined, dried with magnesium sulfate and concentrated in vacuo to an oil. Toluene (50 ml.) is added twice and evaporated in vacuo to remove unwanted low boiling impurities.

The residue is maintained under active vacuum overnight to give 3.38 gm. (7.45 mole) of an oil, that shows no hydroxyl or carboxyl absorption in the infrared. ν max: 1720 cm⁻¹ (unsaturated ketone and silyl ester), 840, 815, 795, 780 cm⁻¹ (silyl ether and silyl ester).

Example 960 Preparation of dl-prostaglandin E₁ and dl-epi-prostaglandin E₁

To a solution of 4.790 g. (0.0091 mole) of 3-(p-anisyldiphenylmethoxy)-trans-1-iodo-1-octene (Example 956) in 5 ml. of toluene cooled to -78° C. under an inert atmosphere is added 3.9 ml. of 2.34 M n-butyllithium in hexane. The resulting solution is warmed to -40° C. and is maintained at this temperature for 1 hour. To the solution containing 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium is then added 3.6 ml. of a 2.44 M solution of trimethylaluminum in heptane and the mixture is allowed to warm to 0° C. The solution containing lithium trimethyl[3-(p-anisyldiphenylmethoxy)-trans-1-octenyl]alanate is then added to a solution of 3.30 g. (0.00726 mole) of 2-(6-carbo-t-butyldimethylsiloxyhexyl)-4-(t-butyldimethylsiloxy)-b 2-cyclopentenone (Example 959) dissolved in 10 ml. of ether cooled to -45° C. under an inert atmosphere. The resulting solution is allowed to warm to room temperature and is stirred at ambient temperatures for 17 hours. The solution is then poured onto a mixture of 5 ml. of concentrated hydrochloric acid and 150 g. of ice. This mixture is stirred until the ice melts and is extracted into ether. The organic phase is washed with ice cold water and cold saturated brine, dried (Na₂ SO₄), and is evaporated (<37° C.) in vacuo. The resulting oil is then heated to 38° C. for 23 hours under an inert atmosphere with 100 ml. of 3:1:1 (V:V:V) acetic acid-tetrahydrofuran-water. The mixture is then evaporated with 150 ml. of xylene in vacuo (<38° C.) to yield an oil. Chromatography of this oil upon 115 g. of Silic AR CC-4 (Mallinckrodt) using a benzene-ethyl acetate gradient as eluent yields dl-prostaglandidn E₁, m.p. 108-112 (from ethyl acetate) and dl-15-epiprostaglandin E₁.

EXAMPLE 961 Preparation of 3-triphenylmethoxy-trans-1-octenyllithium

To a solution of 4.96 g. of 1-iodo-3-triphenylmethoxy-trans-1-octene (Example 730) in 10 ml. of toluene cooled to -78° C. is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is then maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium.

EXAMPLE 962 Preparation of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium

To a solution of 5.26 g. 1-iodo-3-(p-anisyldiphenylmethoxy)-trans-1-octene (Example 956) in 10 ml. of toluene, cooled to 31 78° C., is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium.

EXAMPLE 963 Preparation of lithium [3-triphenylmethoxy-trans-1-octenyl]-trimethylalanate

To a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) cooled to -40° C. is added under an inert atmosphere 1molar equivalent of trimethylaluminum dissolved in heptane to yield a hydrocarbon solution of the title compound.

EXAMPLE 964 Preparation of lithium [3-p-anisyldiphenylmethoxy)-trans-1-octenyl]-trimethylalanate

To a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium (Example 962) cooled to -40° C. is added under an inert atmosphere 1 molar equivalent of trimethylaluminum dissolved in hexane to yield a hydrocarbon solution of the title compound.

EXAMPLE 965 Preparation of lithium [3-triphenylmethoxy-trans-1-octenyl]tri-n-propylalanate

To a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) cooled to -40° C. is added under an inert atmosphere 1molar equivalent of tri-n-propylaluminum dissolved in hexane to yield a hydrocarbon solution of the title compound.

EXAMPLE 966 Preparation of lithium [3-(p-anisyldiphenylmethoxy)-trans-1-octenyl]-tri-n-hexylalanate

To a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium (Example 962) cooled to -40° C. is added under an inert atmosphere 1 molar equivalent to tri-n-hexylaluminum dissolved in heptane to yield a hydrocarbon solution of the title compound.

EXAMPLE 967 Preparation of lithium [3-triphenylmethoxy-trans-1-octenyl]-tri-n-decylalanate

To a hydrocarbon solution of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) cooled to -40° C. is added under an inert atmosphere 1 molar equivalent of tri-n-decylaluminum dissolved in heptane to yield a hydrocarbon solution of the title compound.

EXAMPLE 968 Preparation of lithium di-(3-triphenylmethoxy-trans-1-octenyl)-dimethylalanate

To a hydrocarbon solution of dimethylaluminum chloride cooled to -78° C. is added under an inert atmosphere 2 molar equivalents of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) dissolved in toluene-hexane solvent. The mixture is allowed to warm to 0° C. to yield a hydrocarbon solution of the title compound.

EXAMPLE 969 Preparation of lithium di-[3-(p-anisyldiphenylmethoxy)-trans-1-octenyl]-diethylalanate

To a hexane solution of diethylaluminum chloride cooled to -78° C. is added under an inert atmosphere 2 molar equivalents of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium (Example 962) dissolved in toluene-hexane solvent. The mixture is allowed to warm to 0° C. to yield a hydrocarbon solution of the title compound.

EXAMPLE 970 Preparation of lithium tri-(3-triphenylmethoxy-trans-1-octenyl)-ethylalanate

To a hydrocarbon solution of ethylaluminum dichloride cooled to -78° C. is added under an inert atmosphere 3 molar equivalents of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) dissolved in toluene-hexane solvent. The mixture is allowed to warm to 0° C. to yield a hydrocarbon solution of the title compound.

EXAMPLE 971 Preparation of lithium tetra-(3-triphenylmethoxy-trans-1-octenyl)alanate

To a well stirred mixture of anhydrous aluminum chloride and hexane cooled to -78° C. is added under an inert atmosphere 4 molar equivalents of 3-triphenylmethoxy-trans-1-octenyllithium (Example 961) dissolved in toluene-hexane The mixture is allowed to warm to 0° C. to yield the title compound.

EXAMPLE 972 Preparation of lithium tetra-(3-p-anisyldiphenylmethoxy-trans-1-octenyl)alanate

To a well stirred mixture of anhydrous aluminum chloride and hexane cooled to -78° C. is added under an inert atmosphere 4 molar equivalents of 3-p-anisyldiphenylmethoxy-trans-1-octenyllithium (Example 962) dissolved in toulene-hexane. The mixture is allowed to warm to 0° C. to yield the title compound.

EXAMPLES 973-981

Substitution of lithium trimethyl(3-triphenylmethoxy-trans-1-octenyl)alanate in Example 957 with the lithium alanates of Examples 964, 965, 966, 967, 968, 969, 970, 971 or 972 is productive of the methyl esters of d,1-11-deoxy-prostaglandin E₁ and d,11-deoxy-15-epi-prostaglandin E₁.

EXAMPLES 982-990

Substitution of lithium trimethyl [3-(p-anisyldiphenylmethoxy)-trans-1-octenyl]alanate of Example 960 with the lithium alanates of Examples 965, 966, 967, 968, 969, 970, 971 or 972 is productive of d,1-prostaglandin-E₁ and d,1-15-epi-prostaglandin E₁.

EXAMPLE 991 Preparation of hexanoyl bromide

A mixture of 300 g. of hexanoic acid and 260 g. of phosphorous tribromide is heated at 80° C. for 1.5 hours with stirring and protection from moisture. The mixture is cooled and the upper phase is decanted into a distilling flask. Distillation of this material yields 400 g. of the colorless acid bromide, b.p. 51-53° C. (10 torr.).

EXAMPLE 992 Preparation of 1-bromo-trans-1-octen-3-one

A mixture of 300 g. of aluminum bromide and 250 ml. of 1,2-dibromoethane, cooled in an ice bath and protected from moisture, is saturated with acetylene. To the mixture is added with ice cooling 150 g. of hexanoyl bromide (Example 991) over a period of 20 minutes and the resulting mixture is treated with acetylene until gas uptake ceases. The reaction mixture is poured onto 500 ml. of saturated brine and 500 g. of ice. The resulting mixture is extracted twice with 500 ml. of ether. The combined organic extracts are washed twice with 500 ml. of saturated brine and dried with anhydrous sodium sulfate. To the organic phase is added 5 g. of hydroquinone and the solvent is evaporated in vacuo to yield the crude 1-bromo-trans-1-octen-3-one.

EXAMPLE 993 Preparation of 1-bromo-trans-1-octen-3-ol

To an ice cooled mixture of 20 g. of sodium borohydride in 800 ml. of anhydrous ethanol is added 160 g. of crude 1-bromo-trans-1-octen-3-one (Example 992) over a period of 0.5 hour. The mixture is stirred for 2 hours with ice cooling and is then partitioned between ice water and benzene. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to an oil. Distillation gives the product as an oil, b.p. 66°-68° C. (0.025 torr.).

EXAMPLE 994 Preparation of 4,4-dimethyl-1-octyn-3-ol

To a solution of 20.2 g. (0.220 mole) of lithium acetylide-ethylenediamine complex in 100 ml. of dry dimethylsulfoxide is added 25.6 g. (0.200 mole) of 2,2-dimethyl-1-hexanal, prepared according to the procedure of G. Stork and S.R. Dowd, J. Amer. Chem. Soc., 85, 2178 (1963), in 25 ml. of dimethylsulfoxide at a rate to maintain a temperature of 25° C. (cooling). The mixture is then maintained at 25° C. for 2 hours and is poured onto ice and excess hydrochloric acid. The mixture is extracted with ether and the organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to an oil. Distillation in vacuo yields the product as a colorless oil.

EXAMPLE 995 Preparation of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne

To a solution of 23.1 g. (0.150 mole) of 4,4-dimethyl-1-octyn-3-ol (Example 994) in 126 g. of freshly distilled dihydropyran is added 1 drop of phosphorus oxychloride and the solution is maintained at ambient temperature in a tightly stoppered flask for 20 hours. Five drops of triethylamine are then added and the mixture is evaporated in vacuo to an oil. The oil is chromatographed on 600 g. of silica gel and the product is eluted with 5% ethyl acetate in benzene yielding a colorless oil.

EXAMPLE 996 Preparation of 4,4-dimethyl-1-iodo-trans-1-octen-3ol

To 233 ml. of a 0.43M solution of disiamylborane in diglyme cooled to 0° C. under an inert atmosphere is added 23.8 g. (0.100 mole) 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 995). The mixture is allowed to come to room temperature and is stirred at ambient temperature for 3 hours. The solution is cooled to 0° C. and 22.5 g. (0.30 mole) of triethylamine oxide is added portionwise such that the temperature is maintained at 0°-5° C. The mixture is stirred at 0° C. for 1 hour and is then poured into 150 ml. of 1 N sodium hydroxide followed immediately by a solution of 25.4 g. (0.100 mole) of iodine in 60 ml. of tetrahydrofuran. The mixture is stirred at ambient temperatures for 0.5 hour and poured into 500 ml. of water. The mixture is decolorized by addition of sodium thiosulfate solution and is extracted into ether. The organic phase is washed with water and the solvent is removed in vacuo. The residue is stirred at room temperature for 20 hours with 900 ml. 3:1:1 tetrahydrofuran-acetic acid-water. The solution is evaporated in vacuo and the residue is chromatograhed on silica gel in benzene using 10-20% ethylacetate in benzene.

EXAMPLE 997 Preparation of 4,4-dimethyl-1-iodo-3-triphenylmethoxy-trans-1-octene

Treatment of 11.2 g. (0.0396 mole) of 4,4-dimethyl-1-iodo-trans-1-octen-3-ol (Example 996) with 12.8 g. of triphenylmethyl bromide in 50 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.

EXAMPLE 998 Preparation of 5,5-dimethyl-1-octyn-3-ol

Treatment of 20.2 g. (0.220 mole) of lithium acetylide-ethylenediame complex in 100 ml. of dimethylsulfoxide with 25.6 g. (0.200 mole) of 3,3-dimethylhexanal [prepared according to the procedure of A. W. Burgstahler, J. Amer. Chem. Soc., 82, 4681 (1960)] and distillation of the product, all as described in Example 994 yields the title compound.

EXAMPLE 999 Preparation of 5,5-dimethyl-3-tetrahydropyranyloxy-1-octyne

Treatment of 23.1 g. (0.150 mole) of 5,5-dimethyl-1-octyn-3-ol (Example 998) with 126 g. of dihydropyran and 1 drop of phosphorus oxychloride as described in Example 995 gives the title compound.

EXAMPLE 1000 Preparation of 5,5-dimethyl-1-iodo-trans1-octen-3-ol

Treatment of 23.8 g. (0.100 mole) of 5,5-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 999) successively with 233 ml. of 0.43 M disiamylborane in diglyme, 22.5 g. of trimethylamine oxide, 150 ml. of 1N sodium hydroxide, 25.4 g. of iodine, and 900 ml. of 3:1:1 tetrahydrofuranacetic acid-water as described in Example 996 gives the title compound.

EXAMPLE 1001 Preparation of 5,5-dimethyl-1-iodo-3-triphenylmethoxy-trans-1-octene

Treatment of 6.0 g. of 5,5-dimethyl-1-iodo-trans-1-octen-3-ol (Example 1000) with 6.9 g. of triphenylmethyl bromide in 30 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.

EXAMPLE 1002 Preparation of 4,4-dimethyl-3-triphenylmethoxy-trans-1-octenyl-lithium

Treatment of 4,4-dimethyl-1-iodo-3-triphenylmethoxy-trans-1-octene (Example 997) with n-butyllithium in the manner of Example 961 provides a toluene-hexane solution of the subject trans-vinyl lithium derivative.

EXAMPLE 1003 Preparation of 5,5-dimethyl-3-triphenylmethoxy-trans-1-octenyllithium

Treatment of 5,5-dimethyl-1-iodo-3-triphenylmethoxy-trans-1-octene (Example 1001) with n-butyllithium in the manner of Example 961 provides a toluene-hexane solution of the subject trans-vinyl lithium derivative.

EXAMPLE 1004 Preparation of lithium (4,4-dimethyl-3-triphenylmethoxy-trans-1-octenyl)-trimethylalanate

The subject alanate in hydrocarbon solution is prepared according to the method of Example 963 from a hydrocarbon solution of 4,4-dimethyl-3-triphenylmethoxy-trans-1-octenyllithium (Example 1002) and trimethylaluminum.

EXAMPLE 1005 Preparation of lithium (5,5-dimethyl-3-triphenylmethoxy-trans-1-octenyl)-trimethylalanate

A hydrocarbon solution of the subject alanate is prepared from a hydrocarbon solution of 5,5-dimethyl-3-triphenylmethoxy-trans-1-octenyl lithium (Example 1003) and trimethylaluminum according to the procedure of Example 963.

EXAMPLE 1006-1031

Treatment of the cycloalkenones of Table 16 which follows with the indicated alanates according to the procedure of Example 957 provides the product 16,16-dimethyl or 17,17 -dimethyl 13-trans-prostenoates of the table. The intermediate corresponding 15-O-triphenylmethyl derivatives are obtained prior to treatment with aqueous acetic acid.

                  TABLE 16                                                         ______________________________________                                                                Product from reaction with                                                     lithium (4,4-Dimethyl-3-                                         Starting cyclo-                                                                              triphenylmethoxy-trans-1-                               Exm-     alkenone of   octenyl)trimethylalanate                                ple      Example       (Example 1004)                                          ______________________________________                                         1006     13            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-13-trans-pro-                                                      stenoate                                                1007     23            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-7a,7b-bishomo-                                                     13-trans-prostenoate                                    1008     31            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-2-ethyl-13-                                                        trans-prostenoate                                       1009     41            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-3,3-dimethyl-                                                      13-trans-prostenoate                                    1010     46            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-3-oxa-13-trans-                                                    prostenoate                                             1011     53            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-7-nor-13-trans-                                                    prostenoate                                             1012     70            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-2-fluoro-13-                                                       trans-prostenoate                                       1013     84            n-decyl 9-oxo-15-hydroxy-                                                      16,16-dimethyl-13-trans-                                                       prostenoate                                             1014     99            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-2-methyl-13-                                                       trans-prostenoate                                       1015     111           ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-10a-homo-13-                                                       trans-prostenoate                                       1016     118           ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-3-thia-13-trans-                                                   prostenoate                                             1017     900           methyl 9-oxo-15-hydroxy-16,-                                                   16-dimethyl-5-cis,13-trans-                                                    prostadienoate                                          1018     79            ethyl 9-oxo-15-hydroxy-16,-                                                    16-dimethyl-2-phenyl-13-                                                       trans-prostenoate                                       ______________________________________                                                                Product from reaction with                                                     lithium (5,5-Dimethyl-3-                                         Starting cyclo-                                                                              triphenylmethoxy-trans-1-                               Exam-    alkenone of   octeyl)trimethylalanate                                 ple      Example       (Example 1005)                                          ______________________________________                                         1019     13            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-13-trans-pro-                                                      stenoate                                                1020     23            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-7a,7b-bishomo-                                                     13-trans-prostenoate                                    1021     31            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-2-ethyl-13-                                                        trans-prostenoate                                       1022     41            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-3,3-dimethyl-                                                      13-trans-prostenoate                                    1023     46            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-3-oxa-13-trans-                                                    prostenoate                                             1024     53            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-7-nor-13-trans-                                                    prostenoate                                             1025     70            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-2-fluoro-13-                                                       trans-prostenoate                                       1026     84            n-decyl 9-oxo-15-hydroxy-                                                      17,17-dimethyl-13-trans-                                                       prostenoate                                             1027     99            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-2-methyl-13-                                                       trans-prostenoate                                       1028     111           ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-10a-homo-13-                                                       trans-prostenoate                                       1029     118           ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-3-thia-13-trans-                                                   prostenoate                                             1030     900           methyl 9-oxo-15-hydroxy-                                                       17,17-dimethyl-5-cis,13-                                                       trans-prostadienoate                                    1031     79            ethyl 9-oxo-15-hydroxy-17,-                                                    17-dimethyl-2-phenyl-13-                                                       trans-prostenoate                                       ______________________________________                                    

EXAMPLES 1032-1055

Saponificatin of the 16,16-dimethyl or 17,17-dimethyl 13-trans-prostenoate alkyl esters of Table 17 below by the method of Example 122 provides the corresponding prostenoic acids of the Table.

                  TABLE 17                                                         ______________________________________                                                                Product 16,16-dimethyl or                                         Starting alkyl                                                                              17,17-dimethyl-9-oxo-15-                                Exam-     ester of     hydroxy-13-trans-proste-                                ple       Example      noic acid                                               ______________________________________                                         1032      1006         9-oxo-15-hydroxy-16,16-di-                                                     methyl-13-trans-prostenoic                                                     acid                                                    1033      1007         9-oxo-15-hydroxy-16,16-di-                                                     methyl-7a,7b-bishomo-13-                                                       trans-prostenoic acid                                   1034      1008         9-oxo-15-hydroxy-16,16-di-                                                     methyl-2-ethyl-13-trans-                                                       prostenoic acid                                         1035      1009         9-oxo-15-hydroxy-16,16-di-                                                     methyl-3,3-dimethyl-13-                                                        trans-prostenoic acid                                   1036      1010         9-oxo-15-hydrox-16,16-di-                                                      methyl-3-oxa-13-trans-pro-                                                     stenoic acid                                            1037      1011         9-oxo-15-hydroxy-16,16-di-                                                     methyl-7-nor-13-trans-pro-                                                     stenoic acid                                            1038      1012         9-oxo-15-hydroxy-16,16-di-                                                     methyl-2-fluoro-13-trans-                                                      prostenoic acid                                         1039      1014         9-oxo-15-hydroxy-16,16-di-                                                     methyl-2-methyl-13-trans-                                                      prostenoic acid                                         1040      1015         9-oxo-15-hydroxy-16,16-di-                                                     methyl-10a-homo-13-trans-                                                      prostenoic acid                                         1041      1016         9-oxo-15-hydroxy-16,16-di-                                                     methyl-3-thia-13-trans-                                                        prostenoic acid                                         1042      1017         9-oxo-15-hydroxy-16,16-di-                                                     methyl-5-cis,13-trans-pro-                                                     stadienoic acid                                         1043      1018         9-oxo-15-hydroxy-16,16-di-                                                     methyl-2-phenyl-13-trans-                                                      prostenoic acid                                         1044      1019         9-oxo-15-hydroxy-17,17-di-                                                     methyl-13-trans-prostenoic                                                     acid                                                    1045      1020         9-oxo-15-hydroxy-17,17-di-                                                     methyl-7a,7b-bishomno-13-                                                      trans-prostenoic acid                                   1046      1021         9-oxo-15-hydroxy-17,17-di-                                                     methyl-2-ethyl-13-trans-                                                       prostenoic acid                                         1047      1022         9-oxo-15-hydroxy-17,17-di-                                                     methyl-3,3-dimethyl-13-                                                        trans-prostenoic acid                                   1048      1023         9-oxo-15-hydroxy-17,17-di-                                                     methyl-3-oxa-13-trans-pro-                                                     stenoic acid                                            1049      1024         9-oxo-15-hydroxy-17,17-di-                                                     methyl-7-nor-13-trans-pro-                                                     stenoic acid                                            1050      1025         9-oxo-15-hydroxy-17,17-di-                                                     methyl-2-fluoro-13-trans-                                                      prostenoic acid                                         1051      1027         9-oxo-15-hydroxy-17,17-di-                                                     methyl-2-methyl-13-trans-                                                      prostenoic acid                                         1052      1028         9-oxo-15-hydroxy-17,17-di-                                                     methyl-10a-homo-13-trans-                                                      prostenoic acid                                         1053      1029         9-oxo-15-hydroxy-17,17-di-                                                     methyl-3-thia-13-trans-pro-                                                    stenoic acid                                            1054      1030         9-oxo-15-hydroxy-17,17-di-                                                     methyl-5-cis,13-trans-pro-                                                     stadienoic acid                                         1055      1031         9-oxo-15-hydroxy-17,17-di-                                                     methyl-2-phenyl-13-trans-                                                      prostenoic acid                                         ______________________________________                                    

EXAMPLES 1056-1081

Treatment of the 9-oxo-acids and esters of Table 18 below with lithium perhydro-9b-boraphenalyl hydride by the procedure of Example 737provides the 9α,15-dihydroxy-16,16-dimethyl or 17,17-dimethyl-13-trans-prostenoic acid of the Table.

                  TABLE 18                                                         ______________________________________                                              Starting 9-oxo                                                                             Product 9α-15-Dihydroxy-16,-                                 derivative  16-dimethyl or 17,17-di-                                           of          methyl-13-trans-prostenoic                                    Ex.  Example     acids or esters                                               ______________________________________                                         1056 1032        9α,15-dihydroxy-16,16-di-                                                methyl-13-trans-prostenoic                                                     acid                                                          1057 1033        9α,15-dihydroxy-16,16-di-                                                methyl-7a,7b-bishomo-13-                                                       trans-prostenoic acid                                         1058 1034        9α,15-dihydroxy-16,16-di-                                                methyl-2-ethyl-13-trans-                                                       prostenoic acid                                               1059 1035        9α,15-dihydroxy-16,16-di-                                                methyl-3,3-dimethyl-13-                                                        trans-prostenoic acid                                         1060 1036        9α,15-dihydroxy-16,16-di-                                                methyl-3-oxa-13-trans-pro-                                                     stenoic acid                                                  1061 1037        9α,15-dihydroxy-16,16-di-                                                methyl-7-nor-13-trans-pro-                                                     stenoic acid                                                  1062 1038        9α,15-dihydroxy-16,16-di-                                                methyl-2-fluoro-13-trans-                                                      prostenoic acid                                               1063 1013        n-decyl 9α,15-dihydroxy-16,-                                             16-dimethyl-13-trans-proste-                                                   noate                                                         1064 1039        9α,15-dihydroxy-16,16-di-                                                methyl-2-methyl-13-trans-                                                      prostenoic acid                                               1065 1040        9α,15-dihydroxy-16,16-di-                                                methyl-10a-homo-13-trans-                                                      prostenoic acid                                               1066 1041        9α,15-dihydroxy-16,16-di-                                                methyl-3-thia-13-trans-pro-                                                    stenoic acid                                                  1067 1042        9α,15-dihydroxy-16,16-di-                                                methyl-5-cis,13-trans-                                                         prostadienoic acid                                            1068 1043        9α,15-dihydroxy-16,16-di-                                                methyl-2-phenyl-13-trans-                                                      prostenoic acid                                               1069 1044        9α,15-dihydroxy-17,17-di-                                                methyl-13-trans-prostenoic                                                     acid                                                          1070 1045        9α,15-dihydroxy-17,17-di-                                                methyl-7a,7b-bishomo-13-                                                       trans-prostenoic acid                                         1071 1046        9α,15-dihydroxy-17,17-di-                                                methyl-2-ethyl-13-trans-                                                       prostenoic acid                                               1072 1047        9α,15-dihydroxy-17,17-di-                                                methyl-3,3-dimethyl-13-                                                        trans-prostenoic acid                                         1073 1048        9α,15-dihydroxy-17,17-di-                                                methyl-3-oxa-13-trans-pro-                                                     stenoic acid                                                  1074 1049        9α,15-dihydroxy-17,17-di-                                                methyl-7-nor-13-trans-pro-                                                     stenoic acid                                                  1075 1050        9α,15-dihydroxy-17,17-di-                                                methyl-2-fluoro-13-trans-                                                      prostenoic acid                                               1076 1026        n-decyl 9α,15-dihydroxy-                                                 17,17-dimethyl-13-trans-                                                       prostenoate                                                   1077 1051        9α,15-dihydroxy-17,17-di-                                                methyl-2-methyl-13-trans-                                                      prostenoic acid                                               1078 1052        9α,15-dihydroxy-17,17-di-                                                methyl-10a-homo-13-trans-                                                      prostenoic acid                                               1079 1053        9α,15-dihydroxy-17,17-di-                                                methyl-3-thia-13-trans-                                                        prostenoic acid                                               1080 1054        9α,15-dihydroxy-17,17-di-                                                methyl-5-cis,13-trans-pro-                                                     stadienoic acid                                               1081 1055        9α,15-dihydroxy-17,17-di-                                                methyl-2-phenyl-13-trans-                                                      prostenoic acid                                               ______________________________________                                    

EXAMPLE 1082

A solution of methyl 9-oxo-15-hydroxy-5-cis,13-trans,17-cis-prostatrienoate (Example 374) in tetrahydrofuran is added to 1.1 equivalent of lithium perhydro-9b-boraphenyalyl hydride in tetrahydrofuran at -78° C. After 30 minutes equal volumes of 5% aqueous sodium carbonate and 30% aqueous hydrogen peroxide is added, and the solution is stirred 15 minutes. The solution is diluted with water and extracted with ether. The organic phase is dried (magnesium sulfate) and concentrated in vacuo to give methyl 9α,15α-dihydroxy-5-cis,13-trans,17-cis-prostatrienoate, contaminated with methyl 9β,15α-dihydroxy-5cis,13trans,17cis-prostatienoate. The crude mixture of esters is dissolved in methylene chloride and added to a refluxing solution of 1.2 equivalents of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in methylene chloride. After 5 hours, the solution is cooled and filtered. The filtrate is diluted with two volumes of ether, extracted with 5% aqueous sodium carbonate and dried with magnesium sulfate. The solution is concentrated in vacuo to give methyl 9α -hydroxy-15-oxo-5cis-13-trans, 17cis-prostatrienoate and 9β-hydroxy-15-oxo-5cis,13trans,17cis-prostatrienoate. The crude material is dissolved in benzene and 1.2 equivalents each of triethylamine and trimethylsilyl chloride is added. The triethylamine hydrochloride is removed by filtration and the solution is concentrated in vacuo to give methyl 9α-trimethylsiloxy-15-keto-5cis,13trans,17cis-prostatrienoate and the corresponding 9β-trimethylsiloxy derivative.

The siloxy derivatives are dissolved in ether at 0° C. and 1.05 equivalents of methyl magnesium bromide in ether is added. After the reaction is complete, the solution is poured into saturated aqueous ammonium chloride and extracted with ether. The ether is dried and concentrated in vacuo to give methyl 9α-trimethylsiloxy-15α-hydroxy-15β-methyl-5cis,13trans,17cis-prostatrienoate, and methyl 9α-trimethylsiloxy-15β-hydroxy-15α-methyl-5cis,13trans,17-cis-prostatrienoate, methyl 9β-trimethylsiloxy-15α-hydroxy-15β-methyl-5cis,13trans,17cis-prostatrienoate, and methyl 9β-trimethylsiloxy-15β-hydroxy-15α-methyl 5cis,13trans,17-'cis-prostatrienoate. Hydrolysis of the siloxy functions of each in a solution of methanol, water and acetic acid (approximately 10:1:1, 3 hours ambient temperatures) and gives methyl 9α,15α-dihydroxy-15β-methyl-5cis-13trans,17cis-prostatrienoate, methyl 9α,15β-dihydroxy-15α-methyl-5cis,13trans, 17cis-prostatrienoate, methyl 9β,15α-dihydroxy-15β-methyl-5cis,13trans,17cis-prostatrienoate and methyl 9β,15β-dihydroxy-15α-methyl-5-cis,13trans,17-cis-prostatrienoate separated by dry column chromatography and further purified by partition chromatography saponification (method of Example 122) of each component in 50% aqueous methanol with potassium hydroxide gives the corresponding free acids.

Treatment of a solution of methyl 9α,15α-dihydroxy-15β-methyl-5cis,13trans,17cis-prostatrienoate in methylene chloride with Collins reagent (CrO₃ -pyridine in methylene chloride) gives methyl 9-oxo-15α-hydroxy-15β-methyl-5cis,13-trans,17cis-prostatrienoate, saponification of which (method of Example 122) gives 9-oxo-15α-hydroxy-15β-methyl-5cis,13trans,17cis-prostatrienoate acid.

Similar treatment of the 15β-hydroxy esters gives methyl 9-oxo-15β-hydroxy-15α-methyl-5cis,13trans,17cis-prostatrienoate which gives 9-oxo-15β-hydroxy-15α-methyl-5cis,13trans,17cis-prostatrienoic acid after saponfication.

EXAMPLES 1083-1101

Treatment of the 9-oxo-15-hydroxy prostenoic esters of Table 18A below by the sequence of reactions described in Example 1082 is productive of the 9α,15-dihydroxy-15-methyl and the 9-oxo-15-hydroxy-15-methyl products of the table. Also prepared in the course of these reaction sequences are the ethyl (methyl for Example 1101) esters corresponding to the products of the table, the 9β-hydroxy derivatives corresponding to the listed 9α-hydroxy derivatives and their ethyl esters, the 15-keto derivatives of the 9α- and 9β-hydroxy compounds corresponding to the 9-oxo starting compounds, and the 9α or 9β-trimethyl-silyloxy ethyl esters of the 15-keto and 15-hydroxy-15-methyl compounds. In all cases both the 15α-hydroxy-15β-methyl and the 15β-hydroxy-15α-methyl products and intermediates are obtained. These epimers are separable by chromatographic procedures.

                  TABLE 18A                                                        ______________________________________                                               Starting 9-oxo-                                                          Ex-   15-hydroxy-ester                                                                               Product 15-hydroxy-                                      ample of Example      15-methyl derivative                                     ______________________________________                                         1083  260             9-oxo-15-methyl-15-                                                            hydroxy-2-ethyl-13-                                                            trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-2-ethyl-13-                                                          trans-prostenoic acid                                    1084  261             9-oxo-15-hydroxy-15-                                                           methyl-3,3-dimethyl-                                                           13-trans-prostenoic                                                            acid and 9α,15-di-                                                       hydroxy-15-methyl-                                                             3,3-dimethyl-13-trans-                                                         prostenoic acid                                          1085  262             9-oxo-15-hydroxy-15-                                                           methyl-3-oxa-13-trans-                                                         prostenoic acid and                                                            9α,15-dihydroxy-15-                                                      methyl-3-oxa-13-trans-                                                         prostenoic acid                                          1086  264             9-oxo-15-hydroxy-15-                                                           methyl-2-fluoro-13-                                                            trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-2-fluoro-                                                            13-trans-prostenoic                                                            acid                                                     1087  266             9-oxo-15-hydroxy-15-                                                           methyl-2-phenyl-13-                                                            trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-2-phenyl-                                                            13-trans-prostenoic                                                            acid                                                     1088  267             9-oxo-15-hydroxy-15-                                                           methyl-2-methyl-13-                                                            trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-2-methyl-                                                            13-trans-prostenoic                                                            acid                                                     1089  268             9-oxo-15-hydroxy-15-                                                           methyl-10a-homo-13-                                                            trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-10a-homo-                                                            13-trans-prostenoic                                                            acid                                                     1090  272             9-oxo-15-hydroxy-15-                                                           methyl-3-thia-13-                                                              trans-prostenoic acid                                                          and 9α,15-dihydroxy-                                                     15-methyl-3-thia-13-                                                           trans-prostenoic acid                                    1091  362             9-oxo-15-hydroxy-15-                                                           methyl-3-thia-20-                                                              methyl-13-trans-pro-                                                           stenoic acid and 9α,15-                                                  dihydroxy-15-methyl-3-                                                         thia-20-methyl-13-                                                             trans-prostenoic acid                                    1092  343             9-oxo-15-hydroxy-15-                                                           methyl-2,20-dimethyl-                                                          13-trans-prostenoic                                                            acid and 9α,15-di-                                                       hydroxy-15-methyl-                                                             2,20-dimethyl-13-                                                              trans,prostenoic acid                                    1093  323             9-oxo-15-hydroxy-15-                                                           methyl-3-oxa-20-methyl-                                                        13-trans-prostenoic                                                            acid and 9α,15-di-                                                       hydroxy-15-methyl-3-                                                           oxa-20-methyl-13-                                                              trans-prostenoic acid                                    1094  284             9-oxo-15-hydroxy-15-                                                           methyl-13-trans,17-                                                            cis-prostadienoic acid                                                         and 9α,15-dihydroxy-15-                                                  methyl-13-trans,17-                                                            cis-prostadienoic acid                                   1095  287             9-oxo-15-hydroxy-15-                                                           methyl-7a,7b-bishomo-                                                          13-trans,17-cis-pro-                                                           stadienoic acid and 9a,                                                        15-dihydroxy-15-methyl-                                                        7a,7b-bishomo-13-                                                              trans,17-cis-prosta-                                                           dienoic acid                                             1096  290             9-oxo-15-hydroxy-15-                                                           methyl-3-oxa-13-trans,                                                         17-cis-prostadienoic                                                           acid and 9a,15-dihydro-                                                        xy-15-methyl-3-oxa-13-                                                         trans,17-cis-prosta-                                                           dienoic acid                                             1097  291             9-oxo-15-hydroxy-15-                                                           methyl-7-nor-13-trans,                                                         17-cis-prostadienoic                                                           acid and 9α,15-di-                                                       hydroxy-15-methyl-7-                                                           nor-13-trans,17-cis-                                                           prostadienoic acid                                       1098  292             9-oxo-15-hydroxy-15-                                                           methyl-2-fluoro-13-                                                            trans,17-cis-prosta-                                                           dienoic acid and 9α,                                                     15-dihydroxy-15-methyl-                                                        2-fluoro-13-trans,                                                             17-cis-prostadienoic                                                           acid                                                     1099  293             9-oxo-15-hydroxy-15-                                                           methyl-7a-homo-13-                                                             trans,17-cis-prosta-                                                           dienoic acid and 9α,15-                                                  dihydroxy-15-methyl-7a-                                                        homo-13-trans,17-cis-                                                          prostadienoic acid                                       1100  300             9-oxo-15-hydroxy-15-                                                           methyl-3-thia-13-trans,                                                        17-cis-prostadienoic                                                           acid and 9α,15-di-                                                       hydroxy-15-methyl-3-                                                           thia-13-trans,17-cis-                                                          prostadienoic acid                                       1101  733             9-oxo-15-hydroxy-15-                                                           methyl-13-cis,17-cis-                                                          prostadienoic acid and                                                         9α,15-dihydroxy-15-                                                      methyl-13-cis,17-cis-                                                          prostadienoic acid                                       ______________________________________                                          *methyl 15-hydroxy-9-oxo-13-cis-prostenoate only                         

EXAMPLES 1102-1104

Hydrogenation of the 13-trans-prostenoic acids listed in Table 19 below by the procedure described in Example 699 is productive of the product prostanoic acids of the table. The product epimers are separable by chromatographic procedures.

                  TABLE 19                                                         ______________________________________                                               Starting 15-hy-                                                                droxy-15-methyl-                                                                               Product 15-hydroxy-                                      Ex-   13-trans-pros-  15-methyl-prostanoic                                     ample tenoic acid     acid                                                     ______________________________________                                         1102  9-oxo-15-hydroxy-                                                                              9-oxo-15-hydroxy-15-                                           15-methyl-3-oxa-                                                                               methyl-3-oxa-prostanoic                                        13-trans-pros-  acid                                                           tenoic acid                                                                    (Example 1085)                                                           1103  9α,15-dihydroxy-                                                                         9α,15-dihydroxy-15-                                      15-methyl-3-oxa-                                                                               methyl-3-oxa-pros-                                             13-trans-pros-  tanoic acid                                                    tenoic acid                                                                    (Example 1085)                                                           1104  9-oxo-15-hydroxy-                                                                              9-oxo-15-hydroxy-15-                                           15-methyl-10a-  methyl-10a-homo-pros-                                          homo-13-trans-  tanoic acid                                                    prostenoic acid                                                                (Example 1089)                                                           ______________________________________                                    

EXAMPLE 1105 Preparation of all cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol

A solution of 1.42 g. (10.0 moles) of all-cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-lactol (E. J. Corey and R. Noyori, Tetrahedron Letters, 1970, 311) in 5 ml. of DMSO is added to a stirred solution with the Whttig reagent (E. J. Corey et al, JACS, 91 5675 (1969) also Example 1108 prepared from 13.3 g. (30 moles) of 4-carboxybutyltriphenylphosphonium bromide 2.52 g (60 moles) of 57% sodium hydride dispersion, and 70 ml. of DMSO at 16° C. during 1 minute.

The solution is stirred at ambient temperature for 20 hours and poured into a stirred mixture of methylene chloride, ice, and hydrochloric acid. The organic phase is separated, and the aqueous phase is extracted with methylene chloride, saturated with sodium chloride, and extracted with ether. The combined organic extracts are partitioned with sodium bicarbonate. The aqueous basic extract is acidified with dilute HCl, saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give the crude title compound as an orange oil.

EXAMPLE 1106 Preparation of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone

To a stirred solution of ca. 1.6 moles of crude all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol (Example 1105) in 1.6 ml. of ether is added 1.6 ml. of 4.0 N chromic acid in 4 N sulfuric acid at 0° C. during 9 minutes. After stirring for 5 minutes at 0° C. the solution is diluted with brine, ether, and ethyl acetate. The organic phase is treated with isopropanol, washed with brine and dried over magnesium sulfate. Evaporation of the solvent gives the subject compound as an oil.

EXAMPLE 1107 Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

A solution of 1.0 mmole of all-cis-2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 1106) and 3.0 mmoles of sodium carbonate in 15 ml. of water is allowed to stand at room temperature for 3 hours. The solution is acidified with HCl, saturated with sodium chloride, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of the title compound and the isomeric compound, 2-(6-carboxy-2-cis-hexenyl)-3-hydroxycyclopent-4-en-1-one. Further treatment of this mixture with N/10 sodium hydroxide at room temperature for 30 minutes causes the rearrangement of the latter isomer to the title compound, which is isolated from basic solution as above.

EXAMPLE 1107a Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

Treatment of cis-anti-cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-γ-lactol (E. J. Corey and R. Noyori Tetrahedron Letters, 1970, 311) with 4-carboxybutyltriphenylphosphonium bromide as described in Example 1105 is productive of 2β-(6-carboxy-2-cis-hexenyl)-3α,4α-oxidocyclopentan-1.beta.-ol which on oxidation by the method of Example 1106 provides 2β-(6-carboxy-2-cis-hexenyl)-3α,4α-oxidocyclopentanone, which in time on treatment with aqueous base by the procedure of Example 1107 furnishes the subject compound.

EXAMPLE 1108 Preparation of 4-carboxybutyltriphenylphosphonium bromide

A mixture of 103 g. of 5-bromovalevic acid and 152 g. of triphenylphosphine in 400 ml. of acetonitrile is refluxed for 48 hours, cooled, diluted with 100 ml. of benzene and allowed to crystallize. The crystals are filtered, washed with benzene and ether, to yield colorless material, m.p. 207°-209° C.

EXAMPLES 1109-1111

Treatment of the indicated ω-bromoalkanoic acids of Table 20 below with triphenylphosphine by the method described in Example 1108 produces the phosphonium bromides of the table.

                  TABLE 20                                                         ______________________________________                                         Ex-   Starting ω-bromo-                                                                         Product                                                 ample alkanone acid    Phosphonium bromide                                     ______________________________________                                         1109  4-bromo-n-butyric                                                                               3-carboxypropyltri-                                           acid             phenylphosphonium                                                              bromide                                                 1110  6-bromo-n-hexanoic                                                                              5-carboxypentyltri-                                           acid             phenylphosphonium                                                              bromide                                                 1111  7-bromo-n-hepta- 6-carboxyhexyltri-                                            noic acid        phenylphosphonium                                                              bromide                                                 ______________________________________                                    

EXAMPLES 1112-1114

Treatment of all cis-5-hydroxy-2,3-oxidocyclopentylacetaldehyde-γ-lactol with the Wittig reagent prepared from the indicated phosphonium bromides of Table 21 below, all by the procedure of Example 1105 is productive of the product compounds of the table.

                  TABLE 21                                                         ______________________________________                                               Reagent phos-                                                            Ex-   phonium bromide                                                                               Product                                                   ample of Example     3,4-oxidocyclopentanol                                    ______________________________________                                         1112  1109           all cis-2-(5-carboxy-2-                                                        cis-pentenyl)-3,4-oxi-                                                         docyclopentan-1-ol                                        1113  1110           all cis-2-(7-carboxy-2-                                                        cis-heptenyl)-3,4-oxi-                                                         docyclopentan-1-ol                                        1114  1111           all cis-2-(8-carboxy-2-                                                        cis-octenyl)-3,4-oxi-                                                          docyclopentan-1-ol                                        ______________________________________                                    

EXAMPLES 1115-1117

Oxidation of the cyclopentanols indicated in Table 22 below by the method described in Example 1106 furnishes the corresponding product 3,4-oxidocyclopentanones of the table.

                  TABLE 22                                                         ______________________________________                                               Starting cyclo-                                                                               Product                                                   Ex-   pentan-1-ol of 3,4-oxidocyclopent-                                       ample Example        an-1-one                                                  ______________________________________                                         1115  1112           all cis-2-(5-carboxy-                                                          2-cis-pentenyl)-3,4-                                                           oxidocyclopentan-1-                                                            one                                                       1116  1113           all cis-2-(7-carboxy-                                                          2-cis-heptenyl)-3,4-                                                           oxidocyclopentan-1-                                                            one                                                       1117  1114           all cis-2-(8-carboxy-                                                          2-cis-octenyl)-3,4-                                                            oxidocyclopentan-1-                                                            one                                                       ______________________________________                                    

EXAMPLES 1118-1120

Alkaline treatment of the 3,4-oxidocyclopentanones of Table 23 below by the process described in Example 1107 is productive of the 4-hydroxycyclopentenones of the table.

                  TABLE 23                                                         ______________________________________                                               Starting 3,4-                                                                  oxidocyclo-          Product                                             Ex-   pentanone of         4-hydroxycyclo-                                     ample Example              pent-2-en-1-one                                     ______________________________________                                         1118  115                  2-(5-carboxy-2-                                                                cis-pentenyl)-4-                                                               hydroxycyclo-                                                                  pent-2-en-1-one                                     1119  1116                 2-(7-carboxy-2-                                                                cis-heptenyl)-                                                                 4-hydroxycyclo-                                                                pent-2-en-1-one                                     1120  1117                 2-(8-carboxy-2-                                                                cis-octenyl)-4-                                                                hydroxycyclo-                                                                  pent-2-en-1-one                                     ______________________________________                                    

EXAMPLES 1121-1124

Treatment of the 4-hydroxycyclopent-2-en-1-ones listed in Table 24 below with dihydropyran is productive of the corresponding bis-tetrahydropyranyl ether-ester of the table.

                  TABLE 24                                                         ______________________________________                                              Starting 4-hy-    Product                                                      droxycyclopent-   bis-tetrahydropyranyl                                        2-en-1-one of     ether-                                                  Ex.  Example           ester                                                   ______________________________________                                         1121 1107              4-tetrahydropyranyloxy-                                                        2-(6-carbotetrahydro-                                                          pyranyloxy-2-cis-hexenyl)                                                      cyclopent-2-en-1-one                                    1122 1118              4-tetrahydropyranyloxy-                                                        2-(5-carbotetrahydro-                                                          pyranyloxy-2-cis-pent-                                                         enyl)cyclopent-2-en-1-                                                         one                                                     1123 1119              4-tetrahydropyranyloxy-                                                        2-(7-carbotetrahydro-                                                          pyranyloxy-2-cis-heptenyl)-                                                    cyclopent-2-en-1-one                                    1124 1120              4-tetrahydropyranyloxy-                                                        2-(8-carbotetrahydro-                                                          pyranyloxy-2-cis-octenyl)-                                                     cyclopent-2-en-1-one                                    ______________________________________                                    

EXAMPLES 1125-1130

Treatment of the 4-hydroxycyclopent-2-en-1-ones listed in Table 25 below with the indicated trialkylsilyl chloride by the method described in Example 958 is productive of the bis-trialkylsilyl ether-esters of the table.

                                      TABLe 25                                     __________________________________________________________________________           Starting 4-hydroxy-                                                            cyclopentenone of                                                                         Trialkylsilyl-                                                                         Product                                               Example                                                                              Example    chloride                                                                               bis-trialkylsilyl ether-ester                         __________________________________________________________________________     1125  1107       (CH.sub.3).sub.3 SiCl                                                                  4-trimethylsiloxy-2-(6-carbotrimethyl-                                         siloxy-2-cis-hexenyl)cyclopent-2-en-1-one             1126  1118       (CH.sub.3).sub.2 SiCl 4-trimethylsiloxy-2-(5-carbotrimeth                      yl-                                                                                    siloxy-2-cis-pentenyl)cyclopent-2-en-1-one            1127  1119       (CH.sub.3).sub.3 SiCl                                                                  4-trimethylsiloxy-2-(7-carbotrimethyl-                                         siloxy-2-cis-heptenyl)cyclopent-2-en-1-one            1128  1120       (CH.sub.3).sub.3 SiCl                                                                  4-trimethylsiloxy-2-(8-carbotrimethyl-                                         siloxy-2-cis-octenyl)cyclopent-2-en-1-one             1130  1107       dimethyliso-                                                                           4-dimethylisopropylsiloxy-2-(6-carbodi-                                propyl silyl                                                                           methylisopropylsiloxy-2-cis-hexenyl)cyclo-                             chloride                                                                               pent-2-en-1-one                                       __________________________________________________________________________

EXAMPLE 1131 Preparation of 1-oxo-2-hydroxy-bicyclo[3.3.0]oct-4-ene

A solution of 6.2 g. (50 mole) of the lactone of cis-2-hydroxycyclopent-4-ene-1-acetic acid [P. A. Grieco, J. Org. Chem., 37, 2363 (1972)] in 350 ml. toluene (dried over molecular sieves) is cooled to -75° C. and treated dropwise under nitrogen with 84 ml. 0.89 M diisobutyl aluminum hydride (10.55 g., 74 mole) over a period of about one hour maintaining the temperature at -74 ± 2° C. The resulting clear solution is stirred at -75° C. for two hours and poured with stirring into a mixture of 15 ml. of concentrated hydrochloric acid and 300 ml. of ice water. The mixture is stirred while warming to room temperature. The layers are separated and the aqueous layer is treated with salt and extracted with three small portions of ether. The combined organic portions are dried over sodium sulfate and evaporated at reduced pressure (75° C. water bath) to yield the product (homogeneous by thin layer chromatography) as a pale yellow mobile liquid.

EXAMPLE 1132 Preparation of 1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene

A solution of the sodium salt of dimethyl sulfoxide is prepared by stirring under nitrogen a mixture of 160 ml. dry dimethyl sulfoxide (dried over molecular sieves and a few pellets of calcium hydride) with 6.0 g. (0.25 mole) of sodium hydride (prepared by washing 10.5 g. of 57% sodium hydride dispersion in mineral oil with two 30 ml. portions of hexane.) The mixture is warmed with stirring at 75° C. (oil bath) for 2.5 hours.

This solution is added over about five minutes to a solution under nitrogen of 44 grams (0.1 mole) of 4-carboxybutyltriphenylphosphonium bromide (Example 1108) in 180 ml. of dry dimethyl sulfoxide. The resulting dark reddish brown solution is stirred for ten minutes, cooled to room temperature and treated with a solution of crude 1-oxa-2-hydroxy-bicyclo[3.3.0]oct-4-ene (6.2 g., 50 mole) (Example 1131) in 20 ml. of anhydrous dimethyl sulfoxide. The resulting solution is stirred 16 hours and then treated with 250 ml. of ice water.

This brown solution is extracted with two portions of ether to remove neutral material then made strongly acidic with hydrochloric acid. The solution is extracted into four 100 ml. portions of methylene chloride. The combined methylene chloride extracts are washed with water, then extracted with four 100 ml. portions of 5% sodium bicarbonate. The combined aqueous extracts are washed with methylene chloride and made acidic to Congo Red with concentrated hydrochloric acid. The mixture is extracted with three 100 ml. portions of methylene chloride. The organic extracts are combined, dried over sodium sulfate and the solvent is evaporated at reduced pressure. The residue (an oily solid) is extracted several times with ether and the ethereal extracts are combined and evaporated at reduced pressure to yield the crude product as a dark oil. The product is purified by chromatograph 6 on silica gel, eluting with ether. The product is a colorless liquid.

EXAMPLE 1133 Preparation of 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one

A solution of 3.2 g. (0.5 mole) of 1-hydroxy-2-(6-carboxy-2-cis-hexenyl)cyclopent-3-ene (Example 1132) in 60 ml. of reagent acetone is treated dropwise with a total of 6 ml. of 8N chromic acid in sulfuric acid at 0° C. The oxidation is rather slow. The resulting mixture is dissolved in 200 ml. of water and the solution is extracted with six 50 ml. portions of ether. The combined ethereal extracts are dried over sodium sulfate and the solvent is evaporated at reduced pressure to yield the product as a yellow oil.

EXAMPLE 1134 Preparation of 2-(6-carboxy-2-cis-hexenyl)cyclopent-2-en-1-one

A solution of 3 g. of crude 2-(6-carboxy-2-cis-hexenyl)cyclopent-3-en-1-one (Example 1133) in 100 ml. of 2% sodium hydroxide is stirred at 80° C. under nitrogen for 1.5 hours. The cooled solution is acidified to Congo Red and extracted into ether. The ethereal extracts are dried over sodium sulfate and evaporated at reduced pressure to afford the product.

EXAMPLES 1135-1137

Treatment of 1-oxa-2-hydroxy-bicyclo[3.3.0]oct-4-ene by the procedure described in Example 1132 with the ylids derived from the phosphonium bromides listed in Table 26 below furnished the product 1-hydroxy-cyclopent-3-enes of the table.

                  TABLE 26                                                         ______________________________________                                              Starting phos-    Product                                                      phonium bromide   1-hydroxy-2-(ω-carboxy-                                of                2-cis-alkenyl)cyclopent-                                Ex.  Example           3-enes                                                  ______________________________________                                         1135 1109              1-hydroxy-2-(5-carboxy-                                                        2-cis-pentenyl)cyclo-                                                          pent-3-ene                                              1136 1110              1-hydroxy-2-(7-carboxy-                                                        2-cis-heptenyl)cyclo-                                                          pent-3-ene                                              1137 111               1-hydroxy-2-(8-carboxy-                                                        2-cis-octenyl)cyclo-                                                           pent-3-ene                                              ______________________________________                                    

EXAMPLES 1138-1140

Oxidation of the 1-hydroxycyclopent-3-enes listed in Table 27 below by the procedure described in Example 1133 is productive of the product cyclopent-3-en-1-ones of the table.

                  TABLE 27                                                         ______________________________________                                              Starting 1-        Product                                                     hydroxycyclo-      2-(ω-carboxy-2-cis-                                   pent-3-ene of      alkenyl)cyclopent-3-                                   Ex.  Example            en-1-one                                               ______________________________________                                         1138 1135               2-(5-carboxy-2-cis-                                                            pentenyl)cyclopent-3-                                                          en-1-one                                               1139 1136               2-(7-carboxy-2-cis-                                                            heptenyl)cyclopent-3-                                                          en-1-one                                               1140 1137               2-(8-carboxy-2-cis-                                                            octenyl)cyclopent-3-                                                           en-1-one                                               ______________________________________                                    

EXAMPLES 1141-1143

Base treatment according to the procedure described in Example 1134 of the cyclopent-3-ene-1-ones listed in Table 28 below is productive of the product cyclopent-2-en-1-ones of the table.

                  TABLE 28                                                         ______________________________________                                                  Starting 2-(ω-                                                           carboxy-2-cis-                                                                               Product                                                          alkenyl)cyclo-                                                                               2-(ω-carboxy-2-cis-                               Ex-      pent-3-ene-1- alkenyl)cyclopent-                                      ample    one of Example                                                                               2-en-1-one                                              ______________________________________                                         1141     1138          2-(5-carboxy-2-cis-                                                            pentenyl)cyclopent-                                                            2-en-1-one                                              1142     1139          2-(7-caboxy-2-cis-                                                             heptenyl)cyclopent-                                                            2-en-1-one                                              1143     1140          2-(8-carboxy-2-cis-                                                            octenyl)cyclopent-                                                             en-en-1-one                                             ______________________________________                                    

EXAMPLES 1144-1146

Treatment of the listed 2-(ω-carboxy-2-cis-alkenyl)cyclopent-2-en-1-one of Table 29 below with diazomethane in the usual manner is productive of the product methyl esters of the table.

                  TABLE 29                                                         ______________________________________                                              Starting car- Product                                                          boxylic acid  2-(ω-carbomethoxy-2-cis-                                   of            alkenyl)cyclopent-2-en-                                     Ex.  Example       1-one                                                       ______________________________________                                         1144 1141          2-(5-carboxymethoxy-2-cis-                                                     pentenyl)cyclopent-2-en-                                                       1-one                                                       1145 1142          2-(7-carbomethoxy-2-cis-                                                       heptenyl)cyclopent-2-en-                                                       1-one                                                       1146 1143          2-(8-carbomethoxy-2-cis-                                                       octenyl)cyclopent-2-en-                                                        1-one                                                       ______________________________________                                    

EXAMPLES 1147-1149

Treatment by the procedure of Example 120 of the cyclopentenones listed in Table 30 below with lithium diisobutylmethyl-(3-triphenylmethoxy-1-trans-5-cis-octadienyl) alanate, also prepared by the procedure of Example 120 from 3-triphenylmethoxy-cis-5-en-octyne-1 (Example 139), diisobutylaluminum hydride and methyl lithium, followed by hydrolysis of the intermediate 15-triphenylmethoxy derivatives by treatment with acetic acid-tetrahydrofuran-water (4:2:1) in the manner of Example 121, and then by saponification of the intermediate methyl esters by the process described in Example 122 is productive of the product prostatrienoic acids of the table.

                  TABLE 30                                                         ______________________________________                                                 Starting 2-(ω-                                                   carbomethoxy-2-                                                                        Product                                                                cis-alkenyl)-                                                                          9-oxo-15-hydroxy-5-                                                    Ex-     cyclopent-2-en-                                                                               cis,13-trans,17-cis-                                    ample                                                                          1-one of Example                                                               prostatrienoic acids                                                           ______________________________________                                         1147    1144           9-oxo-4-nor-15-hydroxy-                                 5-cis-13-trans-17-                                                             cis-prostatrienoic                                                                                    acid                                                    1148    1145           9-oxo-4a-homo-15-hydro-                                                        xy-5-cis-13-trans-17-                                   cis-prostatrienoic                                                                                    acid                                                    1149    1146           9-oxo-4a-bishomo-15-hy-                                                        droxy-5-cis-13-trans-                                   17-cis-prostatrienoic                                                                                 acid                                                    ______________________________________                                    

EXAMPLES 1150-1159

Treatment of the ether-ester blocked 4-oxycyclopent-2-en-1-ones listed in Table 31 below with lithium trimethyl[3-(p-anisyldiphenylmethoxy)-trans-1-octenyl] according to the procedure described in Example 960 is productive of the 9-oxo-11α,15-dihydroxy-5-cis,13-trans-prostadienoic acids of the table as well as of the corresponding 15-epi derivatives, separable from the listed 15-normal derivatives by chromatography.

                  TABLE 31                                                         ______________________________________                                                  Starting blocked                                                                             Product                                                          4-oxycyclopent-                                                                              9-oxo-11α,15-dihydroxy-                           Ex-                                                                            2-en-1-one of                                                                  5-cis,13-trans-pros-                                                           ample    Example       tadienoic acids                                         ______________________________________                                         1150     1121          9-oxo-11α,15-dihydroxy-                           5-cis,13-trans-prosta-                                                                                dienoic acid (prosta-                                                          glandin E.sub.2)                                        1151     1125          9-oxo-11α,15-dihydroxy-                           5-cis,13-trans-prosta-                                                                                dienoic acid (prosta-                                                          glandin E.sub.2)                                        1152     1130          9-oxo-11α,15-dihydroxy-                           5-cis,13-trans-prosta-                                                                                dienoic acid (prosta-                                                          glandin E.sub.2)                                        1153     1122          9-oxo-11α,15-dihydroxy-                           4-nor-5-cis,13-trans-                                                          prostadienoic acid                                                             1154     1126          9-oxo-11α,5-dihydroxy-                            4-nor-5-cis,13-trans-                                                          prostadienoic acid                                                             1155     1123          9-oxo-11α,15-dihydroxy-                           4a-homo-5-cis,13-trans-                                                        prostadienoic acid                                                             1156     1127          9-oxo-11α,15-dihydroxy-                           4a-homo-5-cis,13-trans-                                                        prostadienoic acid                                                             1158     1124          9-oxo-11α,15-dihydroxy-                           4a,4b-homo-5-cis,13-                                                           trans-prostadienoic                                                                                   acid                                                    1159     1128          9-oxo-11α,15-dihydroxy-                           4a,4b-homo-5-cis,13-                                                           trans-prostadienoic                                                                                   acid                                                    ______________________________________                                    

EXAMPLES 1160-1169

Treatment by the procedure described in Example 123 of the ether-ester blocked 4-oxycyclopent-2-en-1-ones listed in Table 32 below with lithium diisobutylmethyl(3-triphenylmethoxy-1-trans-5-cis-octadienyl)alanate, prepared from 3triphenylmethoxy-cis-5-en-octyne-1- (Example 139) by the procedure of Example 120, followed by the cleavage of blocking groups and isolation of products by the method described in Example 124 is productive of the 9-oxo-11α,15-dihydroxy-5-cis,13-trans,17-cis-prostatrienoic acids of the table; also formed are the corresponding 15-epi derivatives which are separable by chromatography from the listed 15-normal derivatives.

                  TABLE 32                                                         ______________________________________                                                 Starting blocked                                                                              Product                                                         4-oxycyclopent-                                                                               9-oxo-11α,15-dihydroxy-                           Ex-     2-en-1-one of  5-cis,13-trans,17-cis-                                  ample   Example        prostatrienoic acids                                    ______________________________________                                         1160    1121           9-oxo-11α,15-dihydroxy-                                                  5-cis,13-trans,17-                                                             cis-prostatrienoic                                                             acid (prostaglandin E.sub.3)                            1161    1125           9-oxo-11α,15-dihydroxy-                                                  5-cis,13-trans,17-cis-                                                         prostatrienoic acid                                                            (prostaglandin E.sub.3)                                 1162    1130           9-oxo-11α,15-dihydroxy-                                                  5-cis,13-trans-17,-cis-                                                        prostatrienoic acid                                                            (prostaglandin E.sub.3)                                 1163    1122           9-oxo-11α,15-dihydroxy-                                                  4-nor-5-cis,13-trans,                                                          17-cis-prostatrienoic                                                          acid                                                    1164    1126           9-oxo-11α,15-dihydroxy-                                                  4-nor-5-cis,13-trans,                                                          17-cis-prostatrienoic                                                          acid                                                    1165    1123           9-oxo-11α,15-dihydroxy-                                                  4a-homo-5-cis,13-                                                              trans,17-cis-prosta-                                                           trienoic acid                                           1166    1127           9-oxo-11α,15-dihydroxy-                                                  4a-homo-5-cis,13-                                                              trans,17-cis-prosta-                                                           trienoic acid                                           1168    1124           9-oxo-11α,15-dihydroxy-                                                  4a,4b-bishomo-5-cis,                                                           13-trans,17-cis-prosta-                                                        trienoic acid                                           1169    1128           9-oxo-11α,15-dihydroxy-                                                  4a,4b-bishomo-5-cis-                                                           13-trans,17-cis-prosta-                                                        trienoic acid                                           ______________________________________                                    

EXAMPLE 1170 Preparation of 9-oxo-11α,15-dihydroxy-5-cis,13-cis-prostadienoic acid

Treatment in the manner described in Example 733 of 4-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyloxy-2-cis-hexenyl)cyclopent-2-en-1-one (Example 1121) with the Grignard reagent prepared from magnesium and 1-bromo-3-triphenylmethoxy-trans-1-octene (Example 728) also as described in Example 733 in the presence of cuprous iodide tri-n-butylphosphine complex is productive after chromatography of prostaglandin E₂ and 9-oxo-11α,15-dihydroxy-5-cis,13-cis-prostadienoic acid.

EXAMPLES 1171 and 1172

Treatment of the two 9-oxo derivative listed in Table 33 below with lithium perhydro-9b-boraphenalylhydride in the manner described in Example 737 furnishes the indicated 9α,15-dihydroxy-13-cis-prostenoic acids.

                  TABLE 33                                                         ______________________________________                                                  Starting 9-oxo-                                                                              Product                                                 Ex-      derivative of 9α,15-dihydroxy-13-cis-                           ample    Example       prostenoic acids                                        ______________________________________                                         1171      736          9α,15-dihydroxy-13-cis-                                                  prostenoic acid                                         1172     1170          9α,15-dihydroxy-5-cis-                                                   prostadienoic acid                                      ______________________________________                                    

EXAMPLE 1173 Preparation of 1-bromo-4,4-dimethyl-3-tetrahydropyranyloxy-trans-1-octene

To an ice cooled solution of 3.5 g. (50 moles) of 2-methyl-2-butene in 25 ml. of tetrahydrofuran under an inert atmosphere is added 25 ml. of 1 M diborane in tetrahydrofuran dropwise over 10 minutes. The mixture is stirred at 0°-5° C. for 2 hours and then the solvent is removed under vacuum. The residue is dissolved in 20 ml. of carbon tetrachloride and to the resulting solution cooled to 0° C. is added a solution of 5.25 g. (22 mole) of 4,4-dimethyl-3-tetrahydropyranyloxy-1-octyne (Example 995) in 10 ml. of carbon tetrachloride over 10 minutes. The cooling bath is removed and the mixture is allowed to stir at ambient temperature for 1.5 hours. The mixture is cooled to 0° C. and a solution of 3.52 g. (22 moles) of bromine in 15 ml. of carbon tetrachloride is added over 10 minutes. The cooling bath is removed and the mixture is refluxed for 6 hours under an inert atmosphere. The mixture is cooled and poured into dilute sodium hydroxide solution. The organic phase is washed with water and saturated brine, dried (Na₂ SO₄), and evaporated. The residue is chromatographed upon silica gel and the title compound is isolated with 5% ethyl acetate in benzene.

EXAMPLE 1174 Preparation of 1-bromo-4,4-dimethyl-trans-1-octen-3ol

A mixture of 3.19 g. (10 moles) of 1-bromo-4,4-dimethyl-3-tetrahydropyranyloxy-trans-1-octene (Example 1173) and 90 ml. of 3:1:1 tetrahydrofuran-acetic acid-water is stirred at ambient temperatures for 20 hours. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel. The title compound is isolated using 10-20% ethyl acetate in benzene.

EXAMPLE 1175 Preparation of 1-bromo-4,4-dimethyl-3-triphenylmethoxy-trans-1-octene

Treatment of 1.88 g. (8 moles) of 1-bromo-4,4-dimethyl-trans-1-octen-3-ol (Example 1174) with 2.58 g. (8 moles) of triphenylmethyl bromide in 20 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.

EXAMPLE 1176 Preparation of 1-bromo-5,5-dimethyl-3-tetrahydropyranyloxy-trans-1-octene

Treatment of 7.15 g. (30 moles) of 5,5-dimethyl-3-tetrahyropyranyloxy-1-octyne (Example 999) with 33 moles of disiamylborane in carbon tetrachloride followed by 30 moles of bromide in carbon tetrachloride, refluxing the resulting mixture, and isolation by chromatography on silica gel, all as described in Example 1173 gives the title compound.

EXAMPLE 1177 Preparation of 1-bromo-5,5-dimethyl-trans-1-octen-3-ol

Treatment of 7.35 g. (23 moles) of 1-bromo-5,5-dimethyl-3-tetrahydropyranyloxy-trans-1-octene (Example 1176) with 200 ml. of 3:1:1 tetrahydrofuran-acetic acid-water and purification on silica gel all as described in Example 1174 gives the title compound.

EXAMPLE 1178 Preparation of 1-bromo-5,5-dimethyl-3-triphenylmethoxy-trans-1-octene

Treatment of 3.53 g. (15 moles) of 1-bromo-5,5-dimethyl-trans-1-octen-3-ol (Example 1177) with 4.85 g. (15 moles) of triphenylmethyl bromide in 35 ml. of pyridine and purification on Florisil®, all as described in Example 728 gives the title compound.

EXAMPLE 1179 Preparation of 1-iodo-3-triphenylmethoxy-trans-1-octene

To a mixture of 0.650 g. (16.91 mole) of sodium borohydride and 3.17 g. (45.2 moles) of 2-methyl-2-butene in 40 ml. of diglyme cooled to -5° C. under an inert atmosphere is added over 15 minutes 3.24 g. (22.6 moles) of boron trifluoride ethereate and the resulting mixture is stirred at 0° C for 2 hours. To this mixture is then added over 5 minutes 8.32 g. (22.6 moles) of 3-triphenylmethoxy-1-octyne (Example 119) in 10 ml. of diglyme, the cooling bath is removed, and the mixture is stirred at ambient temperatures for 1.5 hours. The mixture is cooled to 0° C. and 6.0 g. of finely divided anhydrous trimethylamine oxide is added over 10 minutes. The cooling bath is removed and the mixture is stirred at ambient temperatures for 0.5 hour. The mixture is then poured into 200 ml. of 15% sodium hydroxide solution, a solution of 16 g. (63 moles) of iodine in 20 ml. of tetrahydrofuran is added immediately, and the resulting mixture is stirred for 0.5 hour. The organic phase is separated and the aqueous phase is washed with ether. The combined organic phase and washings are decolorized with 5% sodium thiosulfate solution, washed with saturated brine, dried (Na₂ SO₄), and evaporated. The residue is dry-columned chromatographed upon alumina using hexane as eluent and the title compound is isolated as an oil.

EXAMPLE 1180 Preparation of 3-triphenylmethoxy-cis-oct-5-en-1-yne

Treatment of 22 g. of cis-oct-5-en-1-yne-3-ol, prepared according to the procedure of J. Fried, C. H. Lin, J. C. Sih, P. Dalven, G. F. Cooper, J. Amer. Chem. Soc., 94, 4342 (1972), with 58 g. of triphenylmethyl bromide in 100 ml. of pyridine and purification of Florisil®, all as described in Example 728 gives the title compound.

EXAMPLE 1181 Preparation of 1-iodo-3-triphenylmethoxy-trans-1,cis-5-octadiene

Treatment of 20 g. of 3-triphenylmethoxy-cis-oct-5-en-1-yne with 55 moles of disiamylborane in diglyme, followed by trimethylamine oxide, aqueous sodium hydroxide, and iodine, and purification of alumina, all as described in Example 1179, gives the title compound.

EXAMPLE 1182 Preparation of 1-bromo-3-triphenylmethoxy-trans-1,cis-5-octadiene

Treatment of 15 g. of 3-triphenylmethoxy-cis-oct-5-en-l-yne (Example 1180) with 41 moles of disiamylborane in tetrahydrofuran, replacing the solvent with carbontetrachloride, addition of 41 moles of bromine, and refluxing the mixture, all as described in Example 1173, and purification of the material upon Florisil® as described in Example 728 gives the title compound.

EXAMPLE 1183 Preparation of 1-iodo-3-triphenylmethoxy-trans-1-decene

Treatment of 3-triphenylmethoxy-1-decyne (Example 129) with disamylborane, trimethylamine oxide and iodine by the procedure described in Example 1179 is productive of the subject compound.

EXAMPLE 1184 Preparation of 1-iodo-3-triphenylmethoxy-trans-1-nonene

Treatment of 3-triphenylmethoxy-1-nonyne (Example 128) with disiamylborane, trimethylamine oxide and iodine by the process described in Example 1179 is productive of the subject compound.

EXAMPLE 1185 Preparation of 1-bromo-3-triphenylmethoxy-trans-1-decene

Treatment of 3-triphenylmethoxy-1-decyne (Example 129) with disiamylborane and the bromide by the procedure described in Example 1173 is productive of the title compound.

EXAMPLE 1186 Preparation of 1-bromo-3-triphenylmethoxy-trans-1-nonene

Treatment of 3-triphenylmethoxy-1-nonyne (Example 128) with disiamylborane and the bromine by the procedure described in Example 1173 is productive of the title compound.

EXAMPLE 1187 Preparation of the Grignard reagent of 1-bromo-3-triphenylmethoxy-trans-1-ocetane at 33° C.

To a slurry of 0.585 g. (0.0241 g. atom) of magnesium and 5 ml. of tetrahydrofuran under an argon atmosphere is added 2 ml. of a solution of 7.536 (0.0168 mole) of 1-bromo-3-triphenylmethoxy-trans-1-ocetene (Example 728) in 10 ml. of tetrahydrofuran. The mixture is warmed to 35° C. and reaction is initiated with 1 drop of methyl iodide. The reaction is allowed to exotherm to 37° C. and then to cool to 33° C. whereupon the remainder of the halide is added at a rate to maintain 33° C. After complete addition of the halide, the mixture is stirred at 33° C. for 1 hour and is separated from the excess magnesium to yield a tetrahydrofuran solution of the title Grignard reagent.

EXAMPLE 1188 Preparation of 11-deoxy-8β-methyl-prostaglandin E₁ methyl ester, 11-deoxy-8α-methyl-8-iso-prostaglandin E₁ methyl ester, methyl 15-hydroxy-8β -methyl-9-oxo-13-cis-prostenoate, and methyl 15-hydroxy-8α-methyl-9-oxo-8-iso-13-cis-prostenoate

The Grignard reagent, prepared as described in Example 1187 from 0.585 g. of magnesium, 7.536 g. of 1-bromo-3-triphenylmethoxy-trans-1-ocetene (Example 728), and 10 ml. of tetrahydrofuran, is added to an ice cooled solution of 3.76 g. of 2-(6-carbomethoxyhexyl)-2-cyclopentenone (Example 83) and 0.305 g. of copper (I) iodide-tri-n-butylphosphine complex in 10 ml. of tetrahydrofuran over 10 minutes under an inert atmosphere. The mixture is stirred with cooling for 0.5 hour and to it is then added 46 g. of methyl iodide. The cooling bath is removed and the mixture is stirred at ambient temperatures for 48 hours. The mixture is poured into saturated ammonium chloride solution and is extracted into ether. The organic phase is washed with saturated brine and is evaporated. The residue is heated to 80° C. with 100 ml. of 80% aqueous acetic acid for 0.5 hour and the mixture is then evaporated to dryness. The residue is dry-column chromatography upon silica gel using 4:1 benzene-ethyl acetate as eluent to afford a mixture of 11-deoxy-8β-methyl-prostaglandin E₁ methyl ester and 11-deoxy- 8α-methyl-8-iso-prostaglandin E₁ methyl ester and a mixture of methyl 15-hydroxy-8β-methyl-9-oxo-13-cis-prostenoate and methyl 15-hydroxy-8α-methyl-9-oxo-8-iso-13-cis-prostenoate. Further separation of the 8β and 8α is isomers is accomplished by a combination of partition chromatography and thin layer chromatography.

EXAMPLES 1190 - 1205

Treatment by the procedure of Example 1188 of the cyclopentenones listed in Table 34 below with the Grignard reagent, prepared as described in Example 1187 from the listed 1-bromo-3-triphenylmethoxy-1-trans-alkenes, and then with methyl iodide furnishes the product 8α and 8β methyl prostenoates of the table. The products are all obtained via the corresponding 15-O-triphenylmethyl derivatives, which are hydrolytically cleaved as described in Example 1188.

                                      TABLE 34                                     __________________________________________________________________________                     Starting 1-bromo-3-                                                            triphenylmethoxy-1-                                                 Starting cycloalkenene                                                                    trans-alkene of                                                Example                                                                             of Example Example   Product 8-alkyl prostenoates                         __________________________________________________________________________     1190 13         1175      ethyl 8-β-methyl-9-oxo-15-hydroxy-16,16-                                  dimethyl-13-trans-prostenoate                                                  ethyl 8α-methyl-9-oxo-15-hydroxy-16,16-                                  dimethyl-8-iso-13-trans-prostenoate                                            ethyl8β-methyl-9-oxo-15-hydroxy-16,16-                                    dimethyl-13-cis-prostenoate                                                    ethyl 8α-methyl-9-oxo-15-hydroxy-16,16-                                  dimethyl-8-iso-13-cis-prostenoate                    1191 13         1178      ethyl 8β-methyl-9-oxo-15-hydroxy-17,17-                                   dimethyl-13-trans-prostenoate                                                  ethyl 8α-methyl-9-oxo-15-hydroxy-17,17-                                  dimethyl-8-iso-13-trans-prostenoate                                            ethyl 8β-methyl-9-oxo-15-hydroxy-17,17-                                   dimethyl-13-cis-prostenoate                                                    ethyl 8α-methyl-9-oxo-15-hydroxy-17,17-                                  dimethyl-8-iso-13-cis-prostenoate                    1192 13         1182      ethyl 8β-methyl-9-oxo-15-hydroxy-13-trans,                                N                                                                              17-cis-prostadienoate                                                          ethyl 8α-methyl-9-oxo-15-hydroxy-8-iso-13-                               O                                                                              trans,17-cis-prostadienoate                                                    ethyl 8β-methyl-9-oxo-15-hydroxy-13-cis,                                  17-cis-prostadienoate                                                          ethyl 8α-methyl-9-oxo-15-hydroxy-8-iso-                                  13-cis,17-cis-prostadienoate                         1193 13         1185      ethyl 8β-methyl-9-oxo-15-hydroxy-20-ethyl-                                13-trans-prostenoae                                                            ethyl 8α-methyl-9-oxo-15-hydroxy-20-ethyl-                               8-iso-13-trans-prostenoate                                                     ethyl 8β-methyl-9-oxo-15-hydroxy-20-ethyl-                                13-cis-prostenoate                                                             ethyl 8α-methyl-9-oxo-15-hydroxy-8-iso-20-                               ethyl-13-cis-prostenoate                             1194 84         1186      decyl 8β-methyl-9-oxo-15-hydroxy-20-                                      methyl-13-trans-prostenoate                                                    decyl 8α-methyl-9-oxo-15-hydroxy-20-                                     methyl-8-iso-13-trans-prostenoate                                              decyl 8β-methyl-9-oxo-15-hydroxy-20-                                      methyl-13-cis-prostenoate                                                      decyl 8α-methyl-9-oxo-15-hydroxy-20-                                     methyl-8-iso-13-cis-prostenoate                      1195 23          728      ethyl 8β-methyl-9-oxo-15-hydroxy-7a,7b-                                   bishomo-13-trans-prostenoate                                                   ethyl 8α-methyl-9-oxo-15-hydroxy-7a,7b-                                  bishomo-8-iso-13-trans-prostenoate                                             ethyl 8β-methyl-9-oxo-15-hydroxy-7a,7b-                                   bishomo-13-cis-prostenoate                                                     ethyl 8α-methyl-9-oxo-15-hydroxy-7a,7b-                                  bishomo-8-iso-13-cis-prostenoate                     1196 31         1185      ethyl 8β-methyl-9-oxo-15-hydroxy-2,20-                                    bisethyl-13-trans-prostenoate                                                  ethyl 8α-methyl-9-oxo-15-hydroxy-2,20-                                   bisethyl-8-iso-13-trans-prostenoate                                            ethyl 8β-methyl-9-oxo-15-hydroxy-2,20-                                    bisethyl-13-cis-prostenoate                                                    ethyl 8α-methyl-9-oxo-15-hydroxy-2,20-                                   bisethyl-8-iso-13-cis-prostenoate                    1197 46         1175      ethyl 8β-methyl-9-oxo-15-hydroxy-3-oxa-16,                                16-dimethyl-13-trans-prostenoate                                               ethyl 8α-methyl-9-oxo-15-hydroxy-3-oxa-16,                               0                                                                              16-dimethyl-8-iso-13-trans-prostenoate                                         ethyl 8β-methyl-9-oxo-15-hydroxy-3-oxa-16,                                0                                                                              16-dimethyl-13-cis-prostenoate                                                 ethyl 8α-methyl-9-oxo-15-hydroxy-3-oxa-16,                               6                                                                              16-dimethyl-8-iso-13-cis-prostenoate                 1198 46         1182      ethyl 8β-methyl-9-oxo-15-hydroxy-3-oxa-                                   13-trans,17-cis-prostadienoate                                                 ethyl 8α-methyl-9-oxo-15-hydroxy-3-oxa-                                  8-iso-13-trans,17-cis-prosteadienoate                                          ethyl 8β-methyl-9-oxo-15-hydroxy-3-oxa-                                   13-cis,17-cis-prostadienoate                                                   ethyl 8α-methyl-9-oxo-15-hydroxy-3-oxa-                                  8-iso-13-cis,17-cis-prostadienoate                   1199 53         1186      ethyl 8β-methyl-9-oxo-15-hydroxy-7-nor-                                   20-methyl-13-trans-prostenoate                                                 ethyl 8α-methyl-9-oxo-15-hydroxy-7-nor-                                  20-methyl-8-iso-13-trans-prostenoate                                           ethyl 8β-methyl-9-oxo-15-hydroxy-7-nor-                                   20-methyl-13-cis-prostenoate                                                   ethyl 8α-methyl-9-oxo-15-hydroxy-7-nor-                                  20-methyl-8-iso-13-cis-prostenoate                   1200 70         1178      ethyl 8β-methyl-9-oxo-15-hydroxy-2-fluoro-                                17,17-dimethyl-13-trans-prostenoate                                            ethyl 8α-methyl-9-oxo-15-hydroxy-2-fluoro-                               17,17-dimethyl-8-iso-13-trans-prostenoate                                      ethyl 8β-methyl-9-oxo-15-hydroxy-2-fluoro-                                17,17-dimethyl-13-cis-prostenoate                                              ethyl 8α-methyl-9-oxo-15-hydroxy-2-fluoro-                               17,17-dimethyl-8-iso-13-cis-prostenoate              1201 111         728      ethyl 8β-methyl-9-oxo-15-hydroxy-10a-homo-                                13-trans-prostenoate                                                           ethyl 8α-methyl-9-oxo-15-hydroxy-10a-homo-                               8-iso-13-trans-prostenoate                                                     ethyl 8β-methyl-9-oxo-15-hydroxy-10a-homo-                                13-cis-prostenoate                                                             ethyl 8α-methyl-9-oxo-15-hydroxy-10a-homo-                               8-iso-13-cis-prostenoate                             1202 79         1186      ethyl 8β-methyl-9-oxo-15-hydroxy-2-phenyl-                                N                                                                              20-methyl-13-trans-prostenoate                                                 ethyl 8α-methyl-9-oxo-15-hydroxy-2-phenyl-                               O                                                                              20-methyl-8-iso-13-trans-prostenoate                                           ethyl 8β-methyl-9-oxo-15-hydroxy-2-phenyl-                                20-methyl-13-cis-prostenoate                                                   ethyl 8α-methyl-9-oxo-15-hydroxy-2-phenyl-                               N                                                                              20-methyl-8-iso-13-cis-prostenoate                   1203 900        1182      methyl 8β-methyl-9-oxo-15-hydroxy-                                        5-cis,13-trans,17-cis-prostatrienoate                                          methyl 8α-methyl-9-oxo-15-hydroxy-8-iso-                                 5-cis,13-trans,17-cis-prostatrienoate                                          methyl 8β-methyl-9-oxo-15-hydroxy-5-cis,                                  13-cis,17-cis-prostatrienoate                                                  methyl 8α-methyl-9-oxo-15-hydroxy-8-iso-                                 5-cis,13-cis,17-cis-prostatrienoate                  1204 900         728      ethyl 8β-methyl-9-oxo-15-hydroxy-5-cis,                                   13-trans-prostadienoate                                                        ethyl 8α-methyl-9-oxo-15-hydroxy-8-iso-                                  5-cis,13-trans-prostadienoate                                                  ethyl 8β-methyl-9-oxo-15-hydroxy-5-cis,                                   13-cis-prostadienoate                                                          ethyl 8α-methyl-9-oxo-15-hydroxy-8-iso-                                  5-cis,13-cis-prostadienoate                          1205 900        1185      ethyl 8β-methyl-9-oxo-15-hydroxy-20-ethyl-                                O                                                                              5-cis,13-trans-prostadienoate                                                  ethyl 8α-methyl-9-oxo-15-hydroxy-20-ethyl-                               8-iso-5-cis,13-trans-prostadienoate                                            ethyl 8β-methyl-9-oxo-15-hydroxy-20-ethyl-                                5-cis,13-cis-prostadienoate                                                    ethyl 8α-methyl-9-oxo-15-hydroxy-20-ethyl-                               8-iso-5-cis,13-cis-prostadienoate                    __________________________________________________________________________

EXAMPLES 1206-1273

Treatment of the designated 9-oxo-prostenoic acid and ester derivatives listed in Table 35 below with sodium borohydride in ethanol as described in Example 257 gives the product 9α and 9β hydroxy derivatives of the table, which are seperable by standard chromatographic techniques.

                  TABLE 35                                                         ______________________________________                                         Ex-     Starting 9-oxo-                                                                               Product 9-hydroxy                                       ample   derivative     derivatives                                             ______________________________________                                         1206    11-deoxy-8β-                                                                             11-deoxy-8β-methyl-pros-                                   methyl-prosta- taglandin F.sub.1 αand F.sub.1 β                     glandin E.sub.1 meth-                                                                         methyl esters                                                   yl ester                                                                       (Example 1188)                                                         1207    11-deoxy-8α-                                                                            11-deoxy-8α-methyl-8-iso-                                 methyl-8-iso-  prostaglandin F.sub.1 α and                               prostaglandin  F.sub.1 β methyl esters                                    E.sub.1 methyl ester                                                           (Example 1188)                                                         1208    methyl 15-hy-  methyl 9α/β,15-di-                                   droxy-8β-meth-                                                                           hydroxy-8β-methyl-13-                                      yl-9-oxo-13-   cis-prostenoates                                                cis-prostenoate                                                                (Example 1188)                                                         1209    methyl 15-hy-  methyl 9α/β,15-dihydroxy                             droxy-8α-meth-                                                                          8α-methyl-8-iso-13-cis-                                   yl-9-oxo-13-   prostenoates                                                    cis-prosteno-                                                                  ate (Example                                                                   1188)                                                                  1210    ethyl 8β-meth-                                                                           ethyl 8β-methyl-9α/β,15-                        yl-9-oxo-15-   dihydroxy-16,16-dimeth-                                         hydroxy-16-    yl-13-trans-prosteno-                                           16-dimethyl-   ates                                                            13-trans-                                                                      prostenoate                                                                    (Example 1190)                                                         1211    ethyl 8α-meth-                                                                          ethyl 8α-methyl-9α/β,15-                       yl-9-oxo-15-   dihydroxy-16,16-dimeth-                                         hydroxy-16,-   yl-8-iso-13-trans-pros-                                         16-dimethyl-   tenoates                                                        8-iso-13-                                                                      trans-prosten-                                                                 oate (Example                                                                  1190)                                                                  1212    ethyl 8β-meth-                                                                           ethyl 8β-methyl-9α/β,15-                        yl-9-oxo-15-hy-                                                                               dihydroxy-16,16-dimeth-                                         droxy-16,16-   yl-13-cis-prostenoates                                          dimethyl-13-                                                                   cis-prosteno-                                                                  ate (Example                                                                   1190)                                                                  1213    ethyl 8α-meth-                                                                          ethyl 8α -methyl-9α/β,15-                      yl-9-oxo-15-   dihydroxy-16,16-dimeth-                                         hydroxy-16,-   yl-8-iso-13-cis-prosten-                                        16-dimethyl-8- oates                                                           iso-13-cis-                                                                    prostenoate                                                                    (Example 1190)                                                                 ethyl-                                                                 1214    8β-methyl-9-                                                                             ethyl 8β-methyl-9α/β,15-                        oxo-15-hydrox- dihydroxy-17,17-dimeth-                                         y-17,17-dimeth-                                                                               yl-13-trans-prostenoates                                        yl-13-trans-                                                                   prostenoate                                                                    (Example 1191)                                                         1215    ethyl 8α-meth-                                                                          ethyl 8α-methyl-9α/β,15-                       yl-9-oxo-15-   dihydroxy-17,17-dimeth-                                         hydroxy-17,17- yl-8-iso-13-trans-pros-                                         dimethyl-8-    tenoates                                                        iso-13-trans-                                                                  prostenoate                                                                    (Example 1191)                                                         1216    ethyl 8β-meth-                                                                           ethyl 8β-methyl-9α/β,15-                        yl-9-oxo-15-   dihydroxy-17,17-dimeth-                                         hydroxy-17,17- yl-13-cis-prostenoates                                          dimethyl-13-                                                                   cis-prosteno-                                                                  ate (Example                                                                   1191)                                                                  1217    ethyl 8α-meth-                                                                          ethyl 8α-methyl-9α/β,15-                       yl-9-oxo-15-hy-                                                                               dihydroxy-17,17-dimeth-                                         droxy-17,17-di-                                                                               yl-8-iso-13-cis-prosten-                                        methyl-8-iso-  oates                                                           13-cis-prosten-                                                                oate (Example                                                                  1191)                                                                  1218    ethyl 8β-meth-                                                                           ethyl 8β-methyl-9α/β,15-                        yl-9-oxo-15-hy-                                                                               dihydroxy-13-trans,17-                                          droxy-13-trans-                                                                               cis-prostadienoates                                             17-cis-prosta-                                                                 dienoate (Exam-                                                                ple 1192)                                                              1219    ethyl 8α-meth-                                                                          ethyl 8α-methyl-9α/β,15-                       yl-9-oxo-15-hy-                                                                               dihydroxy-8-iso-13-trans                                        droxy-8-iso-13-                                                                               17-cis-prostadienoates                                          trans,17-cis-                                                                  prostadienoate                                                                 (Example 1192)                                                         1220    ethyl 8β-meth-                                                                           ethyl 8β-methyl-9α/β,15-                        yl-9-oxo-15-hy-                                                                               dihydroxy-13-cis,17-                                            droxy-13-cis,- cis-prostadienoates                                             17-cis-prostadi-                                                               enoate (Example                                                                1192)                                                                  1221    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-8-iso-13-cis-                                         droxy-8-iso-13-                                                                               17-cis-prostadienoates                                          cis,17-cis-pros-                                                               tadienoate (Exam-                                                              ple 1192)                                                              1222    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-20-ethyl-13-                                          droxy-20-ethyl-13-                                                                            trans-prostenoates                                              trans-prosteno-                                                                ate (Example 1193)                                                     1223    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-20-ethyl-8-                                           droxy-20-ethyl-8-                                                                             iso-13-trans-prosteno-                                          iso-13-trans-  ates                                                            prostenoate                                                                    (Example 1193)                                                         1224    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-20-ethyl-13-                                          droxy-20-ethyl-13-                                                                            cis-prostenoates                                                cis-prostenoate                                                                (Example 1193)                                                         1225    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-20-ethyl-8-                                           droxy-20-ethyl-                                                                               iso-13-cis-prostenoates                                         8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1193)                                                         1226    decyl 8β-methyl-                                                                         decyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-20-methyl-13-                                         droxy-20-methyl-                                                                              trans-prostenoates                                              13-trans-pros-                                                                 tenoate (Example                                                               1194)                                                                  1127    decyl 8α-methyl-                                                                        decyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-20-methyl-8-                                          droxy-20-methyl-                                                                              iso-13-trans-prosteno-                                          8-iso-13-trans-                                                                               ates                                                            prostenoate                                                                    (Example 1194)                                                         1128    decyl 8β-methyl-                                                                         decyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-20-methyl-13-                                         droxy-20-methyl-                                                                              cis-prostenoates                                                13-cis-prosten-                                                                oate (Example                                                                  1194)                                                                  1229    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-20-methyl-8-                                          droxy-20-methyl-                                                                              iso-13-cis-prostenoates                                         8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1194)                                                         1230    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-7a,7b-bis-                                            droxy-7a,7b-bis-                                                                              homo-13-trans-prosteno-                                         homo-13-trans- ates                                                            prostenoate                                                                    (Example 1195)                                                         1231    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-7a,7b-bis-                                            droxy-7a,7b-bis-                                                                              homo-8-iso-13-trans-                                            homo-8-iso-13- prostenoates                                                    trans-prosteno-                                                                ate (Example                                                                   1195)                                                                  1232    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-7a,7b-bis-                                            droxy-7a,7b-bis-                                                                              homo-13-cis-prosteno-                                           homo-13-cis-pros-                                                                             ates                                                            tenoate (Example                                                               1195)                                                                  1233    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-7a,7b-bis-                                            droxy-7a,7b-bis-                                                                              homo-8-iso-13-cis-pros-                                         homo-8-iso-13- tenoates                                                        cis-prostenoate                                                                (Example 1195)                                                         1234    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2,20-bis-                                             droxy-2,20-bis-                                                                               ethyl-13-trans-prosteno-                                        ethyl-13-trans-                                                                               ates                                                            prostenoate                                                                    (Example 1196)                                                         1235    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2,20-bis-                                             droxy-2,20-bis-                                                                               ethyl-8-iso-13-trans-                                           ethyl-8-iso-13-                                                                               prostenoates                                                    trans-prosteno-                                                                ate (Example                                                                   1196)                                                                  1236    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2,2-bis-                                              droxy-2,20-bis-                                                                               ethyl-13-cis-prosteno-                                          ethyl-13-cis-  ates                                                            prostenoate                                                                    (Example 1196)                                                         1237    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2,20-bis-                                             droxy-2,20-bis-                                                                               ethyl-8-iso-13-cis-pros-                                        ethyl-8-iso-13-                                                                               tenoates                                                        cis-prostenoate                                                                (Example 1196)                                                         1238    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-3-oxa-16,16-                                          droxy-3-oxa-16,                                                                               dimethyl-13-trans-pros-                                         16-dimethyl-13-                                                                               tenoates                                                        trans-prosteno-                                                                ate (Example                                                                   1197)                                                                  1239    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-3-oxa-16,16-                                          droxy-3-oxa-16,-                                                                              dimethyl-8-iso-13-trans-                                        16-dimethyl-8- prostenoates                                                    iso-13-trans-                                                                  prostenoate                                                                    (Example 1197)                                                         1240    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-3-oxa-16,16-                                          droxy-3-oxa-16,-                                                                              dimethyl-13-cis-pros-                                           16-dimethyl-13-                                                                               tenoates                                                        cis-prostenoate                                                                (Example 1197)                                                         1241    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-3-oxa-16,16-                                          droxy-3-oxa-16,-                                                                              dimethyl-8-iso-13-cis-                                          16-dimethyl-8- prostenoates                                                    iso-13-cis-                                                                    prostenoate                                                                    (Example 1197)                                                         1242    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-3-oxa-13-                                             droxy-3-oxa-13-                                                                               trans,17-cis-prostadi-                                          trans,17-cis-  enoates                                                         prostadienoate                                                                 (Example 1198)                                                         1243    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-3-oxa-8-iso-                                          droxy-3-oxa-8- 13-trans,17-cis-prosta-                                         iso-13-trans-  dienoates                                                       17-cis-prostadi-                                                               enoate (Example                                                                1198)                                                                  1244    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-3-oxa-13-cis-                                         droxy-3-oxa-13-                                                                               17-cis-prostadienoates                                          cis,17-cis-pros-                                                               tadienoate (Exam-                                                              ple 1198)                                                              1245    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-3-oxa-8-iso-                                          droxy-3-oxa-8-iso-                                                                            13-cis,17-cis-prosta-                                           13-cis,17-cis- dienoates                                                       prostadienoate                                                                 (Example 1198)                                                         1246    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-7-nor-20-                                             droxy-7-nor-20-                                                                               methyl-13-trans-pros-                                           methyl-13-trans-                                                                              tenoates                                                        prostenoate                                                                    (Example 1199)                                                         1247    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-7-nor-20-                                             droxy-7-nor-20-                                                                               methyl-8-iso-13-trans-                                          methyl-8-iso-13-                                                                              prostenoates                                                    trans-prosteno-                                                                ate (Example 1199)                                                     1248    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-7-nor-20-                                             droxy-7-nor-20-                                                                               methyl-13-cis-prosteno-                                         methyl-13-cis- ates                                                            prostenoate                                                                    (Example 1199)                                                         1249    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-7-nor-20-                                             droxy-7-nor-20-                                                                               methyl-8-iso-13-cis-                                            methyl-8-iso-  prostenoates                                                    13-cis-prosteno-                                                               ate (Example                                                                   1199)                                                                  1250    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2-fluoro-17,-                                         droxy-2-fluoro-                                                                               17-dimethyl-13-trans-                                           17,17-dimethyl-                                                                               prostenoates                                                    13-trans-prosten-                                                              oate (Example                                                                  1200)                                                                  1251    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2-fluoro-17,-                                         droxy-2-fluoro-                                                                               17-dimethyl-8-iso-13-                                           17,17-dimethyl-                                                                               trans-prostenoates                                              8-iso-13-trans-                                                                prostenoate                                                                    (Example 1200)                                                         1252    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2-fluoro-17,-                                         droxy-2-fluoro-17,-                                                                           17-dimethyl-13-cis-pros-                                        17-dimethyl-13-                                                                               tenoates                                                        cis-prostenoate                                                                (Example 1200)                                                         1253    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2-fluoro-17,-                                         droxy-2-fluoro-                                                                               17-dimethyl-8-iso-13-                                           17,17-dimethyl-                                                                               cis-prostenoates                                                8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1200)                                                         1254    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-10a-homo-13-                                          droxy-10a-homo-13-                                                                            trans-prostenoates                                              trans-prosteno-                                                                ate (Example                                                                   1201)                                                                  1255    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-10a-homo-8-                                           droxy-10a-homo-8-                                                                             iso-13-trans-prosteno-                                          iso-13-trans-  ates                                                            prostenoate                                                                    (Example 1201)                                                         1256    ethyl 8β-methyl-                                                                         ethyl 8β -methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-10a-homo-13-                                          droxy-10a-homo-                                                                               cis-prostenoates                                                13-cis-prosten-                                                                oate (Example                                                                  1201)                                                                  1257    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-10a-homo-8-                                           droxy-10a-homo-8-                                                                             iso-13-cis-prostenoates                                         iso-13-cis-pros-                                                               tenoate (Example                                                               1201)                                                                  1258    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2-phenyl-20-                                          droxy-2-phenyl-                                                                               mthyl-13-trans-prosten-                                         20-methyl-13-  oates                                                           trans-prosteno-                                                                ate (Example                                                                   1202)                                                                  1259    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2-phenyl-20-                                          droxy-2-phenyl-                                                                               methyl-8-iso-13-trans-                                          20-methyl-8-iso-                                                                              prostenoates                                                    13-trans-pros-                                                                 tenoate (Example                                                               1202)                                                                  1260    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,15-                        9-oxo-15-hy-   dihydroxy-2-phenyl-20-                                          droxy-2-phenyl-                                                                               methyl-13-cis-prosteno-                                         20-methyl-13-cis-                                                                             ates                                                            prostenoate                                                                    (Example 1202)                                                         1261    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-2-phenyl-20-                                          droxy-2-phenyl-                                                                               methyl-8-iso-13-cis-                                            20-methyl-8-iso-                                                                              prostenoates                                                    13-cis-prosteno-                                                               ates (Example                                                                  1202)                                                                  1262    methyl 8β-methyl-                                                                        methyl 8β-methyl-9α/β,15-                       9-oxo-15-hy-   dihydroxy-5-cis,13-                                             droxy-5-cis,13-                                                                               trans,17-cis-prostatri-                                         trans,17-cis-pros-                                                                            enoates                                                         tatrienoate                                                                    (Example 1203)                                                         1263    methyl 8α-methyl-                                                                       methyl 8α-methyl-9α/β,15-                      9-oxo-15-hy-   dihydroxy-8-iso-5-cis,-                                         droxy-8-iso-5- 13-trans,17-cis-prosta-                                         cis,13-trans,17-                                                                              trienoates                                                      cis-prostatri-                                                                 enoate                                                                         (Example 1203)                                                         1264    methyl 8β-methyl-                                                                        methyl 8β-methyl-9α/β,-                         9-oxo-15-hy-   15-dihydroxy-5-cis,13-                                          droxy-5-cis,13-                                                                               cis,17-cis-prostatri-                                           cis,17-cis-pros                                                                               enoates                                                         tatrienoate                                                                    (Example 1203)                                                         1265    methyl 8α-methyl-                                                                       methyl 8α-methyl-9α/β,15-                      9-oxo-15-hy-   dihydroxy-8-iso-5-cis,-                                         droxy-8-iso-5- 13-cis,17-cis-prostatri-                                        cis,13-cis,17- enoates                                                         cis-prostatrien-                                                               oate (Example                                                                  1203)                                                                  1266    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,-                          9-oxo-15-hy-   15-dihydroxy-5-cis,13-                                          droxy-5-cis,13-                                                                               trans-prostadienoates                                           trans-prostadi-                                                                enoate (Example                                                                1204)                                                                  1267    ethyl 8α-methyl-                                                                        ethyl 8β-methyl-9α/β-                           9-oxo-15-hy-   15-dihydroxy-8-iso-5-                                           droxy-8-iso-5- cis,13-trans-prosta-                                            cis,13-trans-  dienoates                                                       prostadienoate                                                                 (Example 1204)                                                         1268    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,-                          9-oxo-15-hy-   15-dihydroxy-5-cis,13-                                          droxy-5-cis,13-                                                                               cis-prostadienoates                                             cis-prostadien-                                                                oate (Example                                                                  1204)                                                                  1269    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,-                         9-oxo-15-hy-   15-dihydroxy-8-iso-5-                                           droxy-8-iso-5- cis,13-cis-prostadien-                                          cis,13-cis-    oates                                                           prostadienoate                                                                 (Example 1204)                                                         1270    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,-                          9-oxo-15-hy-   15-dihydroxy-20-ethyl-                                          droxy-20-ethyl-                                                                               5-cis,13-trans-prosta-                                          5-cis,13-trans-                                                                               dienoates                                                       prostadienoate                                                                 (Example 1205)                                                         1271    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,-                         9-oxo-15-hy-   15-dihydroxy-20-ethyl-                                          droxy-20-ethyl-8-                                                                             8-iso-5-cis,13-trans-                                           iso-5-cis,13-  prostadienoates                                                 trans-prostadien-                                                              oate (Example                                                                  1205)                                                                  1272    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9α/β,-                          9-oxo-15-hy-   15-dihydroxy-20-ethyl-                                          droxy-20-ethyl-                                                                               5-cis,13-cis-prostadi-                                          5-cis,13-cis-  enoates                                                         prostadienoate                                                                 (Example 1205)                                                         1273    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9α/β,-                         9-oxo-15-hy-   15-dihydroxy-20-ethyl-                                          droxy-20-ethyl-                                                                               8-iso-5-cis,13-cis-                                             8-iso-5-cis,13-                                                                               prostadienoates                                                 cis-prostadien-                                                                oate (Example                                                                  1205)                                                                  ______________________________________                                    

EXAMPLES 1274 - 1299

In the manner of Example 93, the various cyclopentenones of Table 36, which follows, are converted to the corresponding 4-bromo derivatives.

                  TABLE 36                                                         ______________________________________                                                 Starting                                                               Ex-     Cyclopentenone                                                                               Product 4-Bromocyclo-                                    ample   of Example    pentenones                                               ______________________________________                                         1274    13            4-bromo-2-(6-carbeth-                                                          oxyhexyl)-cyclopent-2-                                                         en-1-one                                                 1275    83            4-bromo-2-(6-carbo-                                                            methoxyhexyl)cyclopent-                                                        2-en-1-one                                               1276    15            4-bromo-2-(4-carbeth-                                                          oxybutyl)cyclopent-2-en-                                                       1-one                                                    1277    14            4-bromo-2-(3-carbethoxy-                                                       propyl)cyclopent-2-en-1-                                                       one                                                      1278     2            4-bromo-2-(4-carboxy-                                                          butyl)cyclopent-2-en-                                                          1-one                                                    1279     5            4-bromo-2-(3-carboxy-                                                          propyl)cyclopent-2-en-1-                                                       one                                                      1280    22            4-bromo-(8-carboxy-                                                            octyl)cyclopent-2-en-1-                                                        one                                                      1281    23            4-bromo-2-(8-carbethoxy-                                                       octyl)cyclopent-2-en-1-                                                        one                                                      1282    30            4-bromo-2-6-carboxy-                                                           octyl)cyclopent-2-en-1-                                                        one                                                      1283    31            4-bromo-2-(6-carbethoxy-                                                       octyl)cyclopent-2-en-1-                                                        one                                                      1284    92            4-bromo-2-(6-carboxy-                                                          5,5-dimethylhexyl)cyclo-                                                       pent-2-en-1-one                                          1285    41            4-bromo-2-(6-carbethoxy-                                                       5,5-dimethylhexyl)cyclo-                                                       pent-2-en-1-one                                          1286    45            4-bromo-2-(6-carboxy-5-                                                        oxahexyl)cyclopent-2-                                                          en-1-one                                                 1287    46            4-bromo-2-(6-carbethoxy-                                                       5-oxahexyl)cyclopent-2-                                                        en-1-one                                                 1288    69            4-bromo-2-(6-carboxy-6-                                                        fluorohexyl)cyclopent-                                                         2-en-1-one                                               1289    70            4-bromo-2-(6-carbethoxy-                                                       6-fluorohexyl)cyclopent-                                                       2-en-1-one                                               1290    52            4-bromo-2-(5-carboxy-                                                          pentyl)cyclopent-2-en-1-                                                       one                                                      1291    53            4-bromo-2-(5-carbethoxy-                                                       pentyl)cyclopent-2-en-                                                         1-one                                                    1292    73            4-bromo-2-(7-carboxy-                                                          heptyl)cyclopent-2-en-1-                                                       one                                                      1293    74            4-bromo-2-(7-carbethoxy-                                                       heptyl)cyclopent-2-en-1-                                                       one                                                      1294    78            4-bromo-2-(6-carboxy-6-                                                        phenylhexyl)cyclopent-2-                                                       en-1-one                                                 1295    79            4-bromo-2-(6-carbethoxy-                                                       6-phenylhexyl)cyclopent-                                                       2-en-1-one                                               1296    81            4-bromo-2-(6-carbo-n-                                                          butoxyhexyl)cyclopent-                                                         2-en-1-one                                               1297    82            4-bromo-2-(6-carbo-iso-                                                        propoxyhexyl)-cyclo-                                                           pent-2-en-1-one                                          1298    84            4-bromo-2-(6-carbo-n-                                                          decyloxyhexyl)cyclopent-                                                       2-en-1-one                                               1299    98            4-bromo-2-(6-carboxy-                                                          heptyl)-cyclopent-2-en-                                                        1-one                                                    ______________________________________                                    

EXAMPLE 1300 Preparation of 4-hydroxy-2-(8-carboxyoctyl)cyclopent-2-en-1-one

To a stirred solution of 57.2 g of crude 4-bromo-2-(8-carboxyoctyl)cyclopent-2-en-1-one (Example 1280) in 500 ml. of acetone and 325 ml. of water at 3° C. is added 44.1 g. (0.226 moles) of silver fluoborate during a 15 minute period. The mixture is stirred at 0°-3° C. for 2 hours and filtered. The filtrate is diluted with water, saturated with solid sodium chloride, and extracted with ether. The extract is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. Partition chromatography of the residue on Celite gives white crystals, m.p. 58°-66° C., λ_(max).^(MeOH) = 223 mμ(7800 ); νmax (KBr) = 3340 (hydroxyl groups), 1705 (carbonyl groups), and 1625 cm⁻¹ (olefin group).

EXAMPLE 1301 Preparation of 4-acetoxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one

A mixture of 51.6 g. (0.137 moles) of crude 4-bromo-2-(6-carbethoxyhexyl)cyclopent-2-en-1one (Example 1274), 27 g. (0.162 moles) of silver acetate, and 200 ml. of glacial acetic acid is stirred at reflux for 4.5 hours. The mixture is cooled, and solids removed by filtration. The filtrate is concentrated and extracted with hot hexane. The extract is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated to give an oil. The crude product is distilled at reduced pressure to give a liquid, b.p. 152°-163° C. (0.01 mm); λ_(max).^(MeOH) = 223 mμ (10700); νmax. = 1745 (ester carbonyl groups), 1725 (ketone carbonyl groups), and 1235 cm ⁻¹ (acetoxy group).

EXAMPLES 1302-1326

By the procedure of Example 94 the various 4-bromocyclopentenones of the following Table 37 are solvolyzed in acetone-water in the presence of silver fluoborate to provide the product 4-hydroxycyclopentenones of the Table.

                  Table 37                                                         ______________________________________                                                 Starting 4-bromo                                                                              Product                                                 Ex-     cyclopentenones                                                                               4-Hydroxycyclopent-2-                                   ample   of Example     en-1-ones                                               ______________________________________                                         1302    1274           4-hydroxy-2-(6-carb-                                                           ethoxyhexyl)cyclopent-                                                         2-en-1-one                                              1303    1275           4-hydroxy-2-(6-carbo-                                                          methoxyhexyl)cyclopent-                                                        2-en-1-one                                              1304    1276           4-hydroxy-2-(4-carb-                                                           ethoxybutyl)cyclopent-                                                         2-en-1-one                                              1305    1277           4-hydroxy-2-(3-carb-                                                           ethoxypropyl)cyclopent-                                                        2-en-1-one                                              1306    1278           4-hydroxy-2-(4-carboxy-                                                        butyl)cyclopent-2-en-                                                          1-one                                                   1307    1279           4-hydroxy-2-(3-carboxy-                                                        propyl)cyclopent-2-en-                                                         1-one                                                   1308    1281           4-hydroxy-2-(8-carb-                                                           ethoxyoctyl)cyclopent-                                                         2-en-1-one                                              1309    1282           4-hydroxy-2-(6-carboxy-                                                        octyl)cyclopent-2-en-                                                          1-one                                                   1310    1283           4-hydroxy-2-(6-carb-                                                           ethoxyoctyl)cyclopent-                                                         2-en-1-one                                              1311    1284           4-hydroxy-2-(6-carboxy-                                                        5,5-dimethylhexyl)-                                                            cyclopent-2-en-1-one                                    1312    1285           4-hydroxy-2-(6-carb-                                                           ethoxy-5,5-dimethyl-                                                           hexyl)cyclopent-2-en-                                                          1-one                                                   1313    1286           4-hydroxy-2-(6-carboxy-                                                        5-oxahexyl)cyclopent-                                                          2-en-1-one                                              1314    1287           4-hydroxy-2-(6-carb-                                                           ethoxy-5-oxahexyl)-                                                            cyclopent-2-en-1-one                                    1315    1288           4-hydroxy-2-(6-carboxy-                                                        6-fluorohexyl)cyclo-                                                           pent-2-en-1-one                                         1316    1289           4-hydroxy-2-(6-carb-                                                           ethoxy-6-fluorohexyl)-                                                         cyclopent-2-en-1-one                                    1317    1290           4-hydroxy-2-(5-carboxy-                                                        pentyl)cyclopent-2-en-                                                         1-one                                                   1318    1291           4-hydroxy-2-(5-carb-                                                           ethoxypentyl)cyclo-                                                            pent-2-en-1-one                                         1319    1292           4-hydroxy-2-(7-carboxy-                                                        heptyl)cyclopent-2-en-                                                         1-one                                                   1320    1293           4-hydroxy-2-(7-carb-                                                           ethoxyheptyl)cyclopent-                                                        2-en-1-one                                              1321    1294           4-hydroxy-2-(6-carboxy-                                                        6-phenylhexyl)cyclo-                                                           pent-2-en-1-one                                         1322    1295           4-hydroxy-2-(6-carb-                                                           ethoxy-6-phenylhexyl)-                                                         cyclopent-2-en-1-one                                    1323    1296           4-hydroxy-2-(6-carbo-                                                          n-butoxyhexyl)cyclo-                                                           pent-2-en-1-one                                         1324    1297           4-hydroxy-2-(6-carbo-                                                          isopropoxyhexyl)cyclo-                                                         pent-2-en-1-one                                         1325    1298           4-hydroxy-2-(6-carbo-                                                          n-decyloxyhexyl)cyclo-                                                         pent-2-en-1-one                                         1326    1299           4-hydroxy-2-(6-carboxy-                                                        heptyl)cyclopent-2-en-                                                         1-one                                                   ______________________________________                                    

Examples 1327-1337

By the procedure of Example 95, the various 4-hydroxycyclopentenones of Table 38, which follows, are converted to the tetrahydropyranyl 4-tetrahydropyranyloxycyclopentenone esters of the table.

                  Table 38                                                         ______________________________________                                                                Product Tetrahydropyran-                                        Starting 4-hy  2'-yl 4-tetrahydropy-                                   Ex-     droxycyclopenten-                                                                             ran-2'-yl-oxycyclopent-                                 ample   one of Example 2-en-1-ones                                             ______________________________________                                         1327    1306           4-tetrahydropyran-2'-                                                          yloxy-2-(4-carbotetra-                                                         hydropyran-2'-yloxy-                                                           butyl)cyclopent-2-en-1-                                                        one                                                     1328    1307           4-tetrahydropyran-2'-                                                          yloxy-2-(3-carbotetra-                                                         hydropyran-2'-yloxy-                                                           propyl)cyclopent-2-en-                                                         1-one                                                   1329    1300           4-tetrahydropyran-2'-                                                          yloxy-2-(8-carbotetra-                                                         hydropyran-2'-yloxy-                                                           octyl)cyclopent-2-en-1-                                                        one                                                     1330    1309           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-                                                           octyl)cyclopent-2-en-1-                                                        one                                                     1331    1311           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-                                                           5,5-dimethylhexyl)-                                                            cyclopent-2-en-1-one                                    1332    1313           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-5-                                                         oxahexyl)cyclopent-2-                                                          en-1-one                                                1333    1315           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-6-                                                         fluorohexyl)cyclopent-                                                         2-en-1-one                                              1334    1317           4-tetrahydropyran-2'-                                                          yloxy-2-(5-carbotetra-                                                         hydropyran-2'-yloxy-                                                           Pentyl)cyclopent-2-en-1-                                                       one                                                     1335    1319           4-tetrahydropyran-2'-                                                          yloxy-2-(7-carbotetra-                                                         hydropyran-2'-yloxyhep-                                                        tyl)cyclopent-2-en-1-                                                          one                                                     1336    1321           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-6-                                                         phenylhexyl)cyclopent-                                                         2-en-1-one                                              1337    1326           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbotetra-                                                         hydropyran-2'-yloxy-                                                           heptyl)cyclopent-2-en-                                                         1-one                                                   ______________________________________                                    

EXAMPLE 1338 Preparation of 4-tetrahydropyranyloxy-2-(6-carbethoxyhexyl)-cyclopent-2-en-1-one

To a stirred solution of 674 mg. (2.64 mmoles) of 4-hydroxy-2-(6-carbethoxyhexyl)cyclopent-2-en-1-one (Example 1302) and 2.22 g. (26.4 mmoles) of dihydropyran in 2.6 ml. of methylene chloride is added 5.0 mg. (0.026 mmoles) of p-toluenesulfonic acid monohydrate. After stirring for 20 minutes at room temperature the solution is diluted with ether and poured into saturated sodium chloride solution containing a little sodium bicarbonate. The organic phase is separated and washed with saturated sodium chloride solution. The extract is dried over magnesium sulfate, and volatile matter is evaporated at reduced pressure to give an oil, λ_(max).^(MeOH) = 224 mμ (7950); max. = 1735 (ester carbonyl group), 1710 (ketone carbonyl group), and 1030 cm⁻¹ (tetrahydropyranyloxy group).

EXAMPLE 1339-1352

In the manner of Example 1338 the alkyl 4-hydroxycyclopentenone esters of Table 39, which follows, are converted to the corresponding 4-tetrahydropyranyloxy alkyl esters of the table.

                  TABLE 39                                                         ______________________________________                                                 Starting 4-                                                                    hydroxycyclo-  4-tetrahydropyran-                                      Ex-     pentenone Esters                                                                              2'yloxycyclopent-                                       ample   of Example     2-en-1-one esters                                       ______________________________________                                         1339    1303           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbomethoxy-                                                       hexyl)cyclopent-2-en-1-                                                        one                                                     1340    1304           4-tetrahydropyran-2'-                                                          yloxy-2-(4-carbethoxy-                                                         butyl)cyclopent-2-en-1-                                                        one                                                     1341    1305           4-tetrahydropyran-2'-                                                          yloxy-2-(3-carbethoxy-                                                         propyl)cyclopent-2-en-1-                                                       one                                                     1342    1308           4-tetrahydropyran-2'-                                                          yloxy-2-(8-carbethoxy-                                                         octyl)cyclopent-2-en-1-                                                        one                                                     1343    1310           4-tetrahydropran-2'-                                                           yloxy-2-(6-carbethoxy-                                                         octyl)cyclopent-2-en-1-                                                        one                                                     1344    1312           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbethoxy-5,                                                       5-dimethylhexyl)cyclo-                                                         pent-2-en-1-one                                         1345    1314           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbethoxy-5-                                                       oxahexyl)cyclopent-2-en-                                                       1-one                                                   1346    1316           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbethoxy-6-                                                       fluorohexyl)cyclopent-                                                         2-en-1-one                                              1347    1318           4-tetrahydropyran-2'-                                                          yloxy-2-(5-carbethoxy-                                                         pentyl)cyclopent-2-en-                                                         1-one                                                   1348    1320           4-tetrahydropyran-2'-                                                          yloxy-2-(7-carbethoxy-                                                         heptyl)cyclopent-2-en-1-                                                       one                                                     1349    1322           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbethoxy-6-                                                       phenylhexyl)cyclopent-2-                                                       en-1-one                                                1350    1323           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbo-n-                                                            butoxyhexyl)cyclopent-2-                                                       en-1-one                                                1351    1324           4-tetrahydropyran-2'-                                                          yloxy-2-(6-carbo-iso-                                                          propoxyhexyl)cyclopent-                                                        2-en-1-one                                              1352    1325           4-tetrahydropyran-2' -                                                         yloxy-2-(6-carbo-n-dec-                                                        yloxyhexyl)cyclopent-2-                                                        en-1-one                                                ______________________________________                                    

EXAMPLE 1353 Preparation of 8β-methyl-prostaglandin E₁, 8α-methyl-8-isoprostaglandin E₁, 8β-methyl-9-oxo-11α,15-dihydroxy-13-cis-prostenoic acid, and 8α-methyl-9-oxo-11α,15-dihydroxy-8-iso-13-cis-prostenoic acid

The Grignard reagent, prepared as described in Example 1187 from 1.54 g. of magnesium, 22.5 g. of 1-bromo-3-triphenylmethoxy-trans-1-octene (Example 728), and 30 ml. of tetrahydrofuran, is added to an ice cooled solution of 17.75 g. of 11-tetrahydropyranyloxy-2-(6-carbotetrahydropyranyloxyhexyl)-2-cyclopentenone (Example 95) and 1.25 g. of copper (I) iodide-tri-n-butylphosphine complex in 30 ml. of tetrahydrofuran over 15 minutes under an inert atmosphere. The mixture is stirred with cooling for 0.5 hour. To the mixture is then added 100 g. of methyl iodide, the cooling bath is then removed and the mixture is stirred at ambient temperatures for 48 hours. The mixture is then poured into ice cold saturated ammonium chloride solution and the layers are separated. The aqueous phase is washed with ether and combined organic phase and washings are washed with saturated brine, and evaporated in vacuo. The residue is heated to 45° C. for 5 hours with 840 ml. of 4:2:1 tetrahydrofuran-acetic acid-water under an inert atmosphere and is then evaporated to dryness in vacuo. The residue is chromatographed upon Silic AR CC-4® using a benzene-ethyl acetate gradient as eluent to yield the title compounds as a mixture of 8β-methyl-prostaglandin E₁ and 8α-methyl-8-iso-prostaglandin E₁ and a mixture of 8β-methyl-9-oxo-11α,15-dihydroxy-13-cis-prostenoic acid and 8α-methyl-9-oxo-11α,15-dihydroxy 8-iso-cis-8α isomers; resolution of the mixtures is then accomplished by a combination of partition chromatography and thin-layer chromatography.

EXAMPLES 1354-1386

Treatment of the blocked 4-oxycyclopent-2-en-1-ones listed in Table 40 below by the procedure described in Example 1353 with the Grignard reagents, prepared by the procedure described in Example 1187 from the listed 1-bromo-3-triphenylmethoxy-1-trans-alkenes, and then with methyl iodide furnishes the product 8α- and 8β-methyl prostenoates of the table. The products of Examples 1354-1378 inclusive are initially obtained as the corresponding 15-O-triphenylmethyl-11-O-tetrahydropyranyl tetrahydropyranyl esters. These blocking groups are then cleaved by the procedure described in Example 1353 by treatment at 45° C. for five hours with 4:2:1 tetrahydrofuran:acetic acid:water. The alkyl esters products of Examples 1379-1385 inclusive are obtained initially as the corresponding 15-O-triphenylmethyl-11-O-tetrahydropyranyl derivatives. These 11- and 15-hydroxy blocking groups are then cleaved by the deblocking procedure described in Example 1353. The products of Example 1386 are initially obtained as the corresponding 15-O-triphenylmethyl derivatives, which are cleaved hydrolytically to the listed free 15 -ols by the process described in Example 1353.

                                      TABLE 40                                     __________________________________________________________________________         Starting blocked                                                                        Starting 1-bromo-                                                     4-oxycyclopent-                                                                         3-triphenylmethoxy-                                               Ex- 2-en-1-one of                                                                           1-trans-alkene of                                                 ample                                                                              Example  Example    Product 8-methylprostenoic acid                        __________________________________________________________________________     1354                                                                                95      1175       8β-methyl-9-oxo-11α,15-dihydroxy-16,16-                             N                                                                              dimethyl-13-trans-prostenoic acid                                              8α-methyl-9-oxo-11α,15-dihydroxy-16,16                             -                                                                              dimethyl-8-iso-13-trans-prostenoic acid                                        8β-methyl-9-oxo-11α,15-dihydroxy-16,16-                             dimethyl-13-cis-prostenoic acid                                                8α-methyl-9-oxo-11α,15-dihydroxy-16,16                             -                                                                              dimethyl-8-iso-13-cis-prostenoic acid                  1355                                                                                95      1178       8β-methyl-9-oxo-11α ,15-dihydroxy,17,17                             -                                                                              dimethyl-13-trans-prostenoic acid                                              8α-methyl-9-oxo-11α,15-dihydroxy-17,17                             -                                                                              dimethyl-8-iso-13-trans-prostenoic acid                                        8β-methyl-9-oxo-11α,15-dihydroxy-17,17-                             dimethyl-13-cis-prostenoic acid                                                8α-methyl-9-oxo-11α,15-dihydroxy-17,17                             -                                                                              dimethyl-8-iso-13-cis-prostenoic acid                  1356                                                                                95      1182       8β-methyl-9-oxo-11α ,15-dihydroxy-13-tr                             ans,                                                                           17-cis-prostadienoic acid                                                      8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -13-                                                                           trans,17-cis-prostadienoic acid                                                8β-methyl-9-oxo-11α,15-dihydroxy-13-cis                             ,                                                                              17-cis-prostadienoic acid                                                      8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -13-                                                                           cis,17-cis-prostadienoic acid                          1357                                                                                95      1185       8β-methyl-9-oxo-11α,15-dihydroxy-20-eth                             yl-                                                                            13-trans-prostenoic acid                                                       8α-methyl-9-oxo-11α,15-dihydroxy-20-et                             hyl-                                                                           8-iso-13-trans-prostenoic acid                                                 8β-methyl-9-oxo-11α,15-dihydroxy-20-eth                             yl-                                                                            13-cis-prostenoic acid                                                         8α-methyl-9-oxo-11α,15-dihydroxy-20-et                             hyl-                                                                           8-iso-13-cis-prostenoic acid                           1358                                                                               1327      728       8β-methyl-9-oxo-11α,15-dihydroxy-6,7-di                             nor-                                                                           13-trans-prostenoic acid                                                       8α-methyl-9-oxo-11α,15-dihydroxy-6,7-d                             inor-                                                                          8-iso-13-trans-prostenoic acid                                                 8β  -methyl-9-oxo-11α,15-dihydroxy-6,7-                             cinor-                                                                         13-cis-prostenoic acid                                                         8α-methyl-9-oxo-11α,15-dihydroxy-6,7-d                             inor-                                                                          8-iso-13-cis-prostenoic acid                           1359                                                                               1328     1186       8β-methyl-9-oxo-11α,15-dihydroxy-5,6,7-                             tri-                                                                           nor-20-methyl-13-trans-prostenoic acid                                         8α-methyl-9-oxo-11α,15-dihydroxy-5,6,7                             -tri-                                                                          nor-20- methyl-8-iso-13-trans-prostenoic acid                                  8β-methyl-9-oxo-11α,15-dihydroxy-5,6,7-                             tri-                                                                           nor-20-methyl-13-cis-prostenoic acid                                           8α-methyl-9-oxo-11α,15-dihydroxy-5,6,7                             -tri-                                                                          nor-20-methyl-8-iso-13-cis-prostenoic acid             1360                                                                               1329      728       8β-methyl-9-oxo-11α,15-dihydroxy-7a,7b-                             bis-                                                                           homo-13-trans-prostenoic acid                                                  8α-methyl-9-oxo-11α,15-dihydroxy-7a,7b                             -bis-                                                                          homo-8-iso-13-trans-prostenoic acid                                            8β-methyl-9-oxo-11α,15-dihydroxy-7a,7b-                             bis-                                                                           homo-13-cis-prostenoic acid                                                    8α-methyl-9-oxo-11α,15-dihydroxy-7a,7b                             -bis-                                                                          homo-8-iso-13-cis-prostenoic acid                      1361                                                                               1330      728       8β-methyl-9-oxo-11α,15-dehydroxy-2-ethy                             l-13-                                                                          trans-prostenoic acid                                                          8α-methyl-9-oxo-11α,15-dihydroxy-2-eth                             yl-8-                                                                          iso-13-trans-prostenoic acid                                                   8β-methyl-9-oxo-11α,15-dihydroxy-2-ethy                             l-13-                                                                          cis-prostenoic acid                                                            8α-methyl-9-oxo-11α,15-dihydroxy-2-eth                             yl-8-                                                                          iso-13-cis-prostenoic acid                             1362                                                                               1331     1186       8β-methyl-9-oxo-11α,15-dihydroxy-3,3,20                             -tri-                                                                          methyl-13-trans-prostenoic acid                                                8α-methyl-9-oxo-11α,15-dihydroxy-3,3,2                             0-tri-                                                                         methyl-8-iso-13-trans-prostenoic acid                                          8β-methyl-9-oxo-11α,15-dihydroxy-3,3,20                             -tri-                                                                          methyl-13-cis-prostenoic acid                                                  8α-methyl-9-oxo-11α,15-dihydroxy-3,3,2                             0-tri-                                                                         methyl-8-iso-13-cis-prostenoic acid                    1363                                                                               1332      728       8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             13-                                                                            trans-prostenoic acid                                                          8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -8-iso-                                                                        13-trans-prostenoic acid                                                       8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             13-                                                                            cis-prostenoic acid                                                            8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -8-                                                                            iso-13-cis-prostenoic acid                             1364                                                                               1332     1175       8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             16,16-                                                                         dimethyl-13-trans-prostenoic acid                                              8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -16,16-                                                                        dimethyl-8-iso-13-trans-prostenoic acid                                        8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             16,16-                                                                         dimethyl-13-cis-prostenoic acid                                                8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -16,16-                                                                        dimethyl-8-iso-13-cis-prostenoic acid                  1365                                                                               1332     1182       8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             13-                                                                            trans,17-cis-prostadienoic acid                                                8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -8-iso-                                                                        13-trans,17-cis-prostadienoic acid                                             8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             13-                                                                            cis,17-cis-prostadienoic acid                                                  8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -8-iso-                                                                        13-cis,17-cis-prostadienoic acid                       1366                                                                               1332     1185       8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             20-                                                                            ethyl-13-trans-prostenoic acid                                                 8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -20-                                                                           ethyl-8-iso-13-trans-prostenoic acid                                           8β-methyl-9-oxo-11α,15-dihydroxy-3-oxa-                             20-                                                                            ethyl-13-cis-prostenoic acid                                                   8α-methyl-9-oxo-11α,15-dihydroxy-3-oxa                             -20-                                                                           ethyl-8-iso-13-cis-prostenoic acid                     1367                                                                               1333     1178       8β-methyl-9-oxo-11α,15-dihydroxy-2-fluo                             ro-                                                                            17,17-dimethyl-13-trans-prostenoic acid                                        8α-methyl-9-oxo-11α,15-dihydroxy-2-flu                             oro-                                                                           17,17-dimethyl-8-iso-13-trans-prostenoic acid                                  8β-methyl-9-oxo-11α,15-dihydroxy-2-fluo                             ro-                                                                            17,17-dimethyl-13-cis-prostenoic acid                                          8α-methyl-9-oxo-11α,15-dihydroxy-2-flu                             oro-                                                                           17,17-dimethyl-8-iso-13-cis-prostenoic acid            1368                                                                               1334      728       8β-methyl-9-oxo-11α,15-dihydroxy-7-nor-                             13-                                                                            trans-prostenoic acid                                                          8α-methyl-9-oxo-11α,15-dihydroxy-7-nor                             -8-                                                                            iso-13-trans-prostenoic acid                                                   8β-methyl-9-oxo-11α,15-dihydroxy-7-nor-                             13-                                                                            cis-prostenoic acid                                                            8α-methyl-9-oxo-11α,15-dihydroxy-7-nor                             -8-                                                                            iso-13-cis-prostenoic acid                             1369                                                                               1335     1175       8β-methyl-9-oxo-11α,15-dihydroxy-7a-hom                             o-                                                                             16,16-dimethyl-13-trans-prostenoic acid                                        8α-methyl-9-oxo-11α,15-dihydroxy-7a-ho                             mo-16,16-                                                                      dimethyl-8-iso-13-trans-prostenoic acid                                        8β-methyl-9-oxo-11α,15-dihydroxy-7a-hom                             o-                                                                             16,16-dimethyl-13-cis-prostenoic acid                                          8α-methyl-9-oxo-11α,15-dihydroxy-7a-ho                             mo-                                                                            16,16-dimethyl-8-iso-13-cis-prostenoic acid            1370                                                                               1336      728       8β-methyl-9-oxo-11α,15-dihydroxy-2-phen                             yl-                                                                            13-trans-prostenoic acid                                                       8α-methyl-9-oxo-11α,15-dihydroxy-2-phe                             nyl-                                                                           8-iso-13-trans-prostenoic acid                                                 8β-methyl-9-oxo-11α,15-dihydroxy-2-phen                             yl-                                                                            13-cis-prostenoic acid                                                         8α-methyl-9-oxo-11α,15-dihydroxy-2-phe                             nyl-                                                                           8-iso-13-cis-prostenoic acid                           1371                                                                               1337     1182       8β-methyl-9-oxo-11α,15-dihydroxy-2-meth                             yl-                                                                            13-trans,17-cis-prostadienoic acid                                             8α-methyl-9-oxo-11α,15-dihydroxy-2-met                             hyl-                                                                           8-iso-13-trans,17-cis-prostandienoic acid                                      8β-methyl-9-oxo-11α,15-dihydroxy-2-meth                             yl-                                                                            13-cis,17-cis-prostadienoic acid                                               8α-methyl-9-oxo-11α,15-dihydroxy-2-met                             hyl-                                                                           8-iso-13-cis,17-cis-prostadienoic acid                 1372                                                                               1121     728        8β-methyl-9-oxo-11α,15-dihydroxy-5-cis,                             13-                                                                            trans-prostadienoic acid                                                       8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -5-                                                                            cis,13-trans-prostadienoic acid                                                8β-methyl-9-oxo-11α,15-dihydroxy-5-cis,                             13-                                                                            cis-prostadienoic acid                                                         8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -5-                                                                            cis,13-cis-prostadienoic acid                          1373                                                                               1121     1182       8β-methyl-9-oxo-11α,15-dihydroxy-5-cis,                             13-                                                                            trans,17-cis-prostatrienoic acid                                               8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -5-                                                                            cis,13-trans,17-cis-prostatrienoic acid                                        8β-methyl-9-oxo-11α,15-dihydroxy-5-cis,                             O                                                                              13-cis,17-cis-prostatrienoic acid                                              8α-methyl-9-oxo-11α,15-dihydroxy-8-iso                             -                                                                              5-cis,13-cis,17-cis-prostatrienoic acid                1374                                                                               1121     1175       8β-methyl-9-oxo-11α,15-dihydroxy-16,16-                             0                                                                              methyl-5-cis,13-trans-prostadienoic acid                                       8α-methyl-9-oxo-11α,15-dihydroxy-16,16                             -di-                                                                           methyl-8-iso-5-cis,13-trans-prostadienoic acid                                 8β-methyl-9-oxo-11α,15-dihydroxy-16,16-                             di-                                                                            methyl-5-cis,13-cis-prostadienoic acid                                         8α-methyl-9-oxo-11α,15-dihydroxy-16,16                             -di-                                                                           methyl-8-iso-5-cis,13-cis-prostadienoic acid           1375                                                                               1122     1186       8β-methyl-9-oxo-11α,15-dihydroxy-4-nor-                             20-                                                                            methyl-5-cis,13-trans-prostadienoic acid                                       8α-methyl-9-oxo-11α,15-dihydroxy-4-nor                             -20-                                                                           methyl-8-iso-5-cis,13-trans-prostadienoic acid                                 8β-methyl-9-oxo-11α,15-dihydroxy-4-nor-                             20-                                                                            methyl-5-cis,13-cis-prostadienoic acid                                         8β-methyl-9-oxo-11α,15-dihydroxy-4-nor-                             20-                                                                            methyl-8-iso-5-cis,13-cis-prostadienoic acid           1376                                                                               1123     1178       8β-methyl-9-oxo-11α,15-dihydroxy-4a-hom                             o-17,                                                                          17-dimethyl-5-cis,13-trans-prostadienoic acid                                  8α-methyl-9-oxo-11α,15-dihydroxy-4a-ho                             mo-17,                                                                         17-dimethyl-8-iso-5-cis,13-cis-prostadienoic                                   acid                                                                           8β-methyl-9-oxo-11α,15-dihydroxy-4a-hom                             o-17,                                                                          17-dimethyl-5-cis,13-cis-prostadienoic acid                                    8α-methyl-9-oxo-11α,15-dihydroxy-4a-ho                             mo-17,                                                                         17-dimethyl-8-iso-5-cis,13-cis-prostadienoic                                   acid                                                   1377                                                                               1124     1185       8β-methyl-9-oxo-11α,15-dihydroxy-4a,4b-                             bis-                                                                           homo-20-ethyl-5-cis,13-trans-prostadienoic                                     acid                                                                           8α-methyl-9-oxo-11α,15-dihydroxy-4a,4b                             -bis-                                                                          homo-20-ethyl-8-iso-5-cis,13-trans-prosta-                                     dienoic acid                                                                   8β-methyl-9-oxo-11α,15-dihydroxy-4a,4b-                             bis-                                                                           homo-20-ethyl-5-cis,13-cis-prostadienoic acid                                  8α-methyl-9-oxo-11α,15-dihydroxy-4a,4b                             -bis-                                                                          homo-20-ethyl-8-iso-5-cis,13-cis-prosta-,                                      -   dienoic acid                                       1378                                                                               1124     1182       8β-methyl-9-oxo-11α,15-dihydroxy-4a,4b-                             bis-                                                                           homo-5-cis,13-trans,17-cis-prostatrienoic                                      acid                                                                           8α-methyl-9-oxo-11α                                                ,15-dihydroxy-4a,4b-bis-                                                       homo-8-iso-5-cis,13-trans,17-cis-prosta-                                       trienoic acid                                                                  8β-methyl-9-oxo-11α,15-dihydroxy-4a,4b-                             bis-                                                                           homo-5-cis,13-cis,17-cis-prostatrienoic acid                                   8α-methyl-9-oxo-11α,15-dihydroxy-4a,4b                             -bis-                                                                          homo-8-iso-5-cis,13-cis-17-cis-prostatrienoic                                  acid                                                   1379                                                                               1339     1186       Methyl 8β-methyl-9-oxo-11α,15-dihydroxy                             -20-                                                                           methyl-13-trans-prostenoate                                                    Methyl 8α-methyl-9-oso-11α,15-dihydrox                             y-20-                                                                          methyl-8-iso-13-trans-prostenoate                                              Methyl 8β-methyl-9-oxo-11α,15-dihydroxy                             -20-                                                                           methyl-13-cis-prostenoate                                                      Methyl 8α-methyl-9-oxo-11α,15-dihydrox                             y-20-                                                                          methyl-8-iso-13-cis-prostenoate                        1380                                                                               1342     1182       Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             7a,7b-                                                                         bishomo-13-trans,17-cis-prostadienoate                                         Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -7a,7b-                                                                        bishomo-8-iso-13-trans,17-cis-prostadienoate                                   Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             7a,7b-                                                                         bishomo-13-cis,17-cis-prostadienoate                                           Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -7a,7b-                                                                        bishomo-8-iso-13-cis,17-cis-prostadienoate             1381                                                                               1343     1175       Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             2-                                                                             ethyl-16,16-dimethyl-13-trans-prostenoate                                      Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -2-                                                                            ethyl-16-16-dimethyl-8-iso-13-trans-                                           Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             2-                                                                             ethyl-16,16-dimethyl-13-cis-prostenoate                                        Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -2-                                                                            ethyl-16,16-dimethyl-8-iso-13-cis-prostenoate          1382                                                                               1344     1178       Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             3,3-                                                                           17,17-tetramethyl-13-trans-prostenoate                                         Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -3,3-                                                                          17,17-tetramethyl-8-iso-13-trans-prostenoate                                   Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             3,3-                                                                           17,17-tetramethyl-13-cis-prostenoate                                           Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -3,3-                                                                          17,17-tetramethyl-8-iso-13-cis-prostenoate             1383                                                                               1345     1178       Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             3-oxa-                                                                         17,17-dimethyl-13-trans-prostenoate                                            Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -3-oxa-                                                                        17,17-dimethyl-8-iso-13-trans-prostenoate                                      Ethyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             3-oxa-                                                                         17,17-dimethyl-13-cis-prostenoate                                              Ethyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -3-oxa-                                                                        17,17-dimethyl-8-iso-13-cis-prostenoate                1384                                                                               1350      728       Butyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             13-                                                                            trans-prostenoate                                                              Butyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -8-iso-                                                                        13-trans-prostenoate                                                           Butyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             13-                                                                            cis-prostenoate                                                                Butyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -8-iso-                                                                        13-cis-prostenoate                                     1385                                                                               1352     1182       Decyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             e                                                                              13-trans,17-cis-prostadienoate                                                 Decyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -8-iso-                                                                        13-trans,17-cis-prostadienoate                                                 Decyl 8β-methyl-9-oxo-11α,15-dihydroxy-                             13-                                                                            cis-17-cis-prostadienoate                                                      Decyl 8α-methyl-9-oxo-11α,15-dihydroxy                             -8-iso-                                                                        13-cis,17-cis-prostadienoate                           1386                                                                               1301      728       Ethyl 8β-methyl-9-oxo-11α-acetoxy-15-hy                             droxy-                                                                         13-trans-prostenoate                                                           Ethyl 8α-methyl-9-oxo-11α-acetoxy-15-h                             ydroxy-                                                                        8-iso-13-trans-prostenoate                                                     Ethyl 8β-methyl-9-oxo-11α-acetoxy-15-hy                             droxy-                                                                         13-cis-prostenoate                                                             Ethyl 8αmethyl-9-oxo-11α-acetoxy-15-hy                             droxy-                                                                         8-iso-13-cis-prostenoate                               __________________________________________________________________________

EXAMPLE 1387 Preparation of 8β-methyl-prostaglandin A₁

A mixture of 0.30 g. of 8β-methyl-prostaglandin E₁ (Example 1353) and 10 ml. of 1:9 aqueous acetic acid is heated to 65° C. for 18 hours under an inert atmosphere. The solvent is removed in vacuo and the residue is purified upon Silic AR-CC-4® using a benzene-ethylacetate gradient to yield the title compound.

EXAMPLES 1388-1522

Treatment of the designated 8-methyl-9-oxo-11-hydroxy-prostenoic acid derivatives of Table 41 below with 1:9 aqueous acid and purification all as described in Example 1387 gives the corresponding 8-methyl-9-oxo-10,13-prostadienoic acids and esters of the table.

                  TABLE 41                                                         ______________________________________                                                 Starting 9-oxo-                                                                               Product 8-methyl-9-oxo-                                 Exam-   11-hydroxy     10,13-prostadienoic                                     ple     derivative     acids or esters                                         ______________________________________                                         1388    8α-methyl-8-iso-                                                                        8α-methyl-8-iso-prosta-                                   prostaglandin  glandin A.sub.1                                                 E.sub.1 (Example 1353)                                                 1389    8β-methyl-9-oxo-                                                                         8β-methyl-11α,15-dihy-                               11α,15-dihy-                                                                            droxy-10,13-cis-prosta-                                         droxy-13-cis-  dienoic acid                                                    prostenoic acid                                                                (Example 1353)                                                         1390    8α-methyl-9-oxo-                                                                        8α-methyl-11α,15-dihy-                              11α,15-dihy-                                                                            droxy-8-iso-10,13-cis-                                          droxy-8-iso-13-                                                                               prostadienoic acid                                              cis-prostenoic                                                                 acid (Example                                                                  1353)                                                                  1391    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihy-                                                                            droxy-16,16-dimethyl                                            droxy-16,16-di-                                                                               10,13-trans-prostadie-                                          methyl-13-trans-                                                                              noic acid                                                       prostenoic acid                                                                (Example 1354)                                                         1392    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihy-                                                                            droxy-16,16-dimethyl-                                           droxy-16,16-di-                                                                               8-iso-10,13-trans-pro-                                          methyl-8-iso-13-                                                                              stadienoic acid                                                 trans-proste-                                                                  noic acid (Exam-                                                               ple 1354)                                                              1393    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-16,16-dimethyl                                            xy-16,16-di-   10,13-cis-prostadienoic                                         methyl-13-cis- acid                                                            prostenoic acid                                                                (Example 1354)                                                         1394    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-16,16-dimethyl-                                           xy-16,16-di-   8-iso-10,13-cis-pro-                                            methyl-8-iso-13-                                                                              stadienoic acid                                                 cis-prostenoic                                                                 acid (Example                                                                  1354)                                                                  1395    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-17,17-dimethyl                                            xy-17,17-di-   10,13-trans-prostadie-                                          methyl 13-trans-                                                                              noic acid                                                       prostenoic acid                                                                (Example 1355)                                                         1396    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-17,17-dimethyl-                                           xy-17,17-di-   8-iso-10,13-trans-pro-                                          methyl-8-iso-13-                                                                              stadienoic acid                                                 trans-prostenoic                                                               acid (Example                                                                  1355)                                                                  1397    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-17,17-dimethyl                                            xy-17,17-di-   10,13-cis-prostadie-                                            methyl 13-cis- noic acid                                                       prostenoic acid                                                                (Example 1355)                                                         1398    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-17,17-dimethyl-                                           xy-17,17-di-   8-iso-10,13-cis-pro-                                            methyl-8-iso-13-                                                                              stadienoic acid                                                 cis-prostenoic                                                                 acid (Example                                                                  1355)                                                                  1399    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-10,13-trans,17-                                           xy-13-trans,17-                                                                               cis-prostatrienoic                                              cis-prostadi-  acid                                                            enoic acid                                                                     (Example 1356)                                                         1400    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-8-iso-10,13-trans,-                                       xy-8-iso-13-   17-cis-prostatrienoic                                           trans,17-cis-  acid                                                            prostadienoic                                                                  acid (Example                                                                  1356)                                                                  1401    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-10,13-cis,17-cis-                                         xy-13-cis,17-cis-                                                                             prostatrienoic acid                                             prostadienoic                                                                  acid (Example                                                                  1356)                                                                  1402    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-8-iso-10,13-cis,-                                         xy-8-iso-13-cis,-                                                                             17-cis-prostatrienoic                                           17-cis-prostadi-                                                                              acid                                                            enoic acid                                                                     (Example 1356)                                                         1403    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-20-ethyl-10,13-                                           xy-20-ethyl-13-                                                                               trans-prostadienoic                                             trans-proste-  acid                                                            noic acid (Exam-                                                               ple 1357)                                                              1404    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-20-ethyl-8-iso-                                           xy-20-ethyl-8- 10,13-trans-prostadi-                                           iso-13-trans-  enoic acid                                                      prostenoic acid                                                                (Example 1357)                                                         1405    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-20-ethyl-10,13-                                           xy-20-ethyl-13-                                                                               cis-prostadienoic acid                                          cis-prostenoic                                                                 acid (Example                                                                  1357)                                                                  1406    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-20-ethyl-8-iso-                                           xy-20-ethyl-8- 10,13-cis-prostadie-                                            iso-13-cis-pro noic acid                                                       stenoic acid                                                                   (Example 1357)                                                         1407    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-6,7-dinor-10,13-                                          xy-6,7-dinor-13-                                                                              trans-prostadienoic                                             trans-proste-  acid                                                            noic acid (Exam-                                                               ple 1358)                                                              1408    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-6,7-dinor-8-iso-                                          xy-6,7-dinor-8-                                                                               10,13-trans-prostadie-                                          iso-13-trans-  noic acid                                                       prostenoic acid                                                                (Example 1358)                                                         1409    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-6,7-dinor-10,13-                                          xy-6,7-dinor-13-                                                                              cis-prostadienoic acid                                          cis-prostenoic                                                                 acid (Example                                                                  1358)                                                                  1410    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-6,7-dinor-8-iso-                                          xy-6,7-dinor-8-                                                                               10,13-cis-prostadie-                                            iso-13-cis-pro-                                                                               noic acid                                                       stenoic acid                                                                   (Example 1358)                                                         1411    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5,6,7-trinor-20-                                          xy-5,6,7-trinor-                                                                              methyl 10,13-trans-                                             20-methyl 13-  prostadienoic acid                                              trans-prostenoic                                                               acid (Example                                                                  1359)                                                                  1412    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-5,6,7-trinor-20-                                          xy-5,6,7-trinor-                                                                              methyl-8-iso-10,13-                                             20-methyl-8-iso-                                                                              trans-prostadienoic                                             13-trans-pro-  acid                                                            stenoic acid                                                                   (Example 1359)                                                         1413    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5,6,7-trinor-20-                                          xy-5,6,7-trinor-                                                                              methyl 10,13-cis-pro-                                           20-methyl 13-  stadienoic acid                                                 cis-prostenoic                                                                 acid (Example                                                                  1359)                                                                  1414    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-5,6,7-trinor-20-                                          xy-5,6,7-trinor-                                                                              methyl-8-iso-10,13-                                             20-methyl-8-   cis-prostadienoic acid                                          iso-13-cis-pro-                                                                stenoic acid                                                                   (Example 1359)                                                         1415    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-7a,7b-bishomo-                                            xy-7a,7b-bishomo-                                                                             10,13-trans-prostadie-                                          13-trans-pro-  noic acid                                                       stenoic acid                                                                   (Example 1360)                                                         1416    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7a,7b-bishomo-                                            xy-7a,7b-bishomo-                                                                             8-iso-10,13-trans-                                              8-iso-13-trans-                                                                               prostadienoic acid                                              prostenoic acid                                                                (Example 1360)                                                         1417    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-7a,7b-bishomo-                                            xy-7a,7b-bishomo-                                                                             10,13-cis-prostadie-                                            13-cis-proste- noic acid                                                       noic acid (Exam-                                                               ple 1360)                                                              1418    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7a,7b-bishomo-                                            xy-7a,7b-bishomo-                                                                             8-iso-10,13-cis-pro-                                            8-iso-13-cis-  stadienoic acid                                                 prostenoic acid                                                                (Example 1360)                                                         1419    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-ethyl-10,13-                                            xy-2-ethyl-13- trans-prostadienoic                                             trans-proste-  acid                                                            noic acid (Exam-                                                               ple 1361)                                                              1420    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-ethyl-8-iso-                                            xy-2-ethyl-8-  10,13-trans-prostadi-                                           iso-13-trans-  enoic acid                                                      prostenoic acid                                                                (Example 1361)                                                         1421    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-ethyl-10,13-                                            xy-2-ethyl-13- cis-prostadienoic acid                                          cis-prostenoic                                                                 acid (Example                                                                  1361)                                                                  1422    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-ethyl-8-iso-                                            xy-2-ethyl-8-  10,13-cis-prostadie-                                            iso-13-cis-pro-                                                                               noic acid                                                       stenoic acid                                                                   (Example 1361)                                                         1423    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3,3,20-trimethyl-                                         xy-3,3,20-tri- 10,13-trans-prostadi-                                           methyl-13-trans-                                                                              enoic acid                                                      prostenoic acid                                                                (Example 1362)                                                         1424    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3,3,20-trimethyl-                                         xy-3,3,20-tri- 8-iso-10,13-trans-pro-                                          methyl-8-iso-13-                                                                              stadienoic acid                                                 trans-proste-                                                                  noic acid                                                                      (Example 1362)                                                         1425    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3,3,20-trimethyl-                                         xy-3,3,20-tri- 10,13-cis-prostadie-                                            methyl-13-cis- noic acid                                                       prostenoic acid                                                                (Example 1362)                                                         1426    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3,3,20-trimethyl-                                         xy-3,3,20-tri- 8-iso-10,13-cis-pro-                                            methyl-8-iso-13-                                                                              stadienoic acid                                                 cis-prostenoic                                                                 acid (Example                                                                  1362)                                                                  1427    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-10,13-trans-                                        xy-3-oxa-13-   prostadienoic acid                                              trans-proste-                                                                  noic acid (Exam-                                                               ple 1363)                                                              1428    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-8-iso-10,-                                          xy-3-oxa-8-iso-                                                                               13,trans-prostadienoic                                          13-trans-proste-                                                                              acid                                                            noic acid (Exam-                                                               ple 1363)                                                              1429    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-10,13-cis-                                          xy-3-oxa-13-cis-                                                                              prostadienoic acid                                              prostenoic acid                                                                (Example 1363)                                                         1430    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-8-iso-10,-                                          xy-3-oxa-8-iso-                                                                               13-cis-prostadienoic                                            13-cis-proste- acid                                                            noic acid (Exam-                                                               ple 1363)                                                              1431    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-16,16-di-                                           xy-3-oxa-16,16-                                                                               methyl-10,13-trans-pro-                                         dimethyl-13-   stadienoic acid                                                 trans-proste-                                                                  noic acid (Exam-                                                               ple 1364)                                                              1432    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         ,-                                                              xy-3-oxa-16,16-                                                                               methyl-8-iso-10,13-                                             dimethyl-8-iso-                                                                               trans-prostadienoic                                             13-trans-proste-                                                                              acid                                                            noic acid (Exam-                                                               ple 1364)                                                              1433    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-16,16-di-                                           xy-3-oxa-16,16-                                                                               methyl-10,13-cis-pro-                                           dimethyl-13-cis-                                                                              stadienoic acid                                                 prostenoic acid                                                                (Example 1364)                                                         1434    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-16,16-di-                                           xy-3-oxa-16,16-                                                                               methyl-8-iso-10,13-cis-                                         dimethyl-8-iso-                                                                               prostadienoic acid                                              13-cis-proste-                                                                 noic acid (Exam-                                                               ple 1364)                                                              1435    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-10,13-                                              xy-3-oxa-13-   trans,17-cis-prosta-                                            trans,17-cis-  trienoic acid                                                   prostadienoic                                                                  acid (Example                                                                  1365)                                                                  1436    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-8-iso-10,-                                          xy-3-oxa-8-iso-                                                                               13-trans,17-cis-pro-                                            13-trans,17-cis-                                                                              statrienoic acid                                                prostadienoic                                                                  acid (Example                                                                  1365)                                                                  1437    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-10,13-cis,-                                         xy-3-oxa-13-cis,                                                                              17-cis-prostatrienoic                                           17-cis-prosta- acid                                                            dienoic acid                                                                   (Example 1365)                                                         1438    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-8-iso-10,-                                          xy-3-oxa-8-iso-                                                                               13-cis,17-cis-prosta-                                           13-cis,17-cis- trienoic acid                                                   prostadienoic                                                                  acid (Example                                                                  1365)                                                                  1439    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro                                                                          droxy-3-oxa-20-ethyl-                                           xy-3-oxa-20-   10,13-trans-prostadie-                                          ethyl-13-trans-                                                                               noic acid                                                       prostenoic acid                                                                (Example 1366)                                                         1440    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-20-ethyl-                                           xy-3-oxa-20-   8-iso-10,13-trans-                                              ethyl-8-iso-13-                                                                               prostadienoic acid                                              trans-proste-                                                                  noic acid ,11α,-                                                                        ple 1366)                                               1441    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-3-oxa-20-ethyl-                                           xy-3-oxa-20-   10,13-cis-prostadie-                                            ethyl-13-cis-  noic acid                                                       prostenoic acid                                                                (Example 1366)                                                         1442    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-3-oxa-20-ethyl-                                           xy-3-ox-20-    8-iso-10,13-cis-pro-                                            ethyl-8-iso-13-                                                                               stadienoic acid                                                 cis-prostenoic                                                                 acid (Example                                                                  1366)                                                                  1443    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-fluoro-17,17-                                           xy-2-fluoro-17,-                                                                              dimethyl-10,13-trans-                                           17-dimethyl-13-                                                                               prostadienoic acid                                              trans-proste-                                                                  noic acid (Exam-                                                               ple 1367)                                                              1444    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-fluoro-17,17-                                           xy-2-fluoro-17,-                                                                              dimethyl-8-iso-10,13-                                           17-dimethyl-8- trans-prostadienoic                                             iso-13-trans-  acid                                                            prostenoic acid                                                                (Example 1367)                                                         1445    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-fluoro-17,17-                                           xy-2-fluoro-17,-                                                                              dimethyl-10,13-cis-                                             17-dimethyl-13-                                                                               prostadienoic acid                                              cis-prostenoic                                                                 acid (Example                                                                  1367)                                                                  1446    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-fluoro-17,17-                                           xy-2-fluoro-17,-                                                                              dimethyl-8-iso-10,13-                                           17-dimethyl-8- cis-prostadienoic acid                                          iso-13-cis-pro-                                                                stenoic acid                                                                   (Example 1367)                                                         1447    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-7-nor-10,13-trans-                                        xy-7-nor-13-   prostadienoic acid                                              trans-proste-                                                                  noic acid (Exam-                                                               ple 1368)                                                              1448    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7-nor-8-iso-10,-                                          xy-7-nor-8-iso-                                                                               13-trans-prostadienoic                                          13-trans-pro-  acid                                                            stenoic acid                                                           methyl-9-oxo-11α1368)                                                    1449    8β/β8β-methyl-9-oxo-15-hy-                                      11α,15-dihydro-                                                                         droxy-7-nor-10,13-cis-                                          xy-7-nor-13-cis-                                                                              prostadienoic acid                                              prostenoic acid                                                                (Example 1368)                                                         1450    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7-nor-8-iso-10,-                                          xy-7-nor-8-iso-                                                                               13-cis-prostadienoic                                            13-cis-proste- acid                                                            noic acid (Exam-                                                               ple 1368)                                                              1451    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-7a-homo-16,16-                                            xy-7a-homo-16,-                                                                               dimethyl-10,13-trans-                                           16-dimethyl-13-                                                                               prostadienoic acid                                              trans-proste-                                                                  noic acid (Exam-                                                               ple 1369)                                                              1452    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7a-homo-16,16-                                            xy-7a-homo-16,-                                                                               dimethyl-8-iso-10,13-                                           16-dimethyl-8- trans-prostadienoic                                             iso-13-trans-  acid                                                            prostenoic acid                                                                (Example 1369)                                                         1453    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-7a-homo-16,16-                                            xy-7a-homo-16,-                                                                               dimethyl-10,13-cis-                                             16-dimethyl-13-                                                                               prostadienoic acid                                              cis-prostenoic                                                                 acid (Example                                                                  1369)                                                                  1454    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-7a-homo-16,16-                                            xy-7a-homo-16,-                                                                               dimethyl-8-iso-10,13-                                           16-dimethyl-8- cis-prostadienoic acid                                          iso-13-cis-pro-                                                                stenoic acid                                                                   (Example 1369)                                                         1455    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-phenyl-10,13-                                           xy-2-phenyl-13-                                                                               trans-prostadienoic                                             trans-prostenoic                                                                              acid                                                            acid (Example                                                                  (Example -1456 8α-methyl-9-oxo- 8α-methyl-9-oxo-15-hy-                            N                                                               11α,15-dihydro-                                                                         droxy-2-phenyl-8-iso-                                           xy-2-phenyl-8- 10,13-trans-prostadi-                                           iso-13-trans-  enoic acid                                                      prostenoic acid                                                                (Example 1370)                                                         1457    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-phenyl-10,13-                                           xy-2-phenyl-13-                                                                               cis-prostadienoic acid                                          cis-prostenoic                                                                 acid (Example                                                                  1370)                                                                  1458    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-phenyl-8-iso-                                           xy-2-phenyl-8- 10,13-cis-prostadie-                                            iso-13-cis-pro-                                                                               noic acid                                                       stenoic acid                                                                   (Example 1370)                                                         1459    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-methyl-10,13-                                           xy-2-methyl-13-                                                                               trans,17-cis-prosta-                                            trans,17-cis-  trienoic acid                                                   prostadienoic                                                                  acid (Example                                                                  1371)                                                                  1460    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-methyl-8-iso-                                           xy-2-methyl-8- 10,13-trans,17-cis-                                             iso-13-trans,- prostatrienoic acid                                             17-cis-prostadi-                                                               enoic acid                                                                     (Example 1371)                                                         1461    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-2-methyl-10,13-                                           xy-2-methyl-13-                                                                               cis,17-cis-prostatri-                                           cis,17-cis-pro-                                                                               enoic acid                                                      stadienoic acid                                                                (Example 1371)                                                         1462    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-2-methyl-8-iso-                                           xy-2-methyl-8- 10,13-cis,17-cis-pro-                                           iso-13-cis,17- statrienoic acid                                                cis-prostadie-                                                                 noic acid (Exam-                                                               ple 1371)                                                              1463    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5,cis,10,13-trans-                                        xy-5,cis,13-   prostatrienoic acid                                             trans-prosta-                                                                  dienoic acid                                                                   (Example 1372)                                                         1464    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-8-iso-5,cis,10,-                                          xy-8-iso-5,cis,-                                                                              13-trans-prostatrienoic                                         13-trans-prosta-                                                                              acid                                                            dienoic acid                                                                   (Example 1372)                                                         1465    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5,cis,10,13-cis-                                          xy-5,cis,13-cis-                                                                              prostatrienoic acid                                             prostadienoic                                                                  acid (Example                                                                  1372)                                                                  1466    8β-methyl-9-oxo-                                                                         8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-8-iso-5,cis,10,13-                                        xy-8-iso,5,cis,-                                                                              cis-prostatrienoic acid                                         13-cis-prostadi-                                                               enoic acid                                                                     (Example 1372)                                                         1467    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5-cis,10,13-                                              xy-5-cis,13-   trans,17-cis-prosta-                                            trans,17-cis-  tetraeneoic acid                                                prostatrienoic                                                                 acid (Example                                                                  1373)                                                                  1468    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy- - 11α,15-dihydro                            - droxy-8-iso-5-cis,10,-                                        xy-8-iso-5-cis,-                                                                              13-trans,17-cis-prosta-                                         13-trans,17-cis-                                                                              tetraneoic acid                                                 prostatrienoic                                                                 acid (Example                                                                  1373)                                                                  1469    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-5-cis,10,13-cis,-                                         xy-5-cis,13-cis,-                                                                             17-cis-prostatetrae-                                            17-cis-prosta- neoic acid                                                      trienoic acid                                                                  (Example 1373)                                                         1470    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-8-iso-5-cis,10-                                           xy-8-iso-5-cis,-                                                                              13-cis,17-cis-prostate-                                         13-cis,17-cis- traeneoic acid                                                  prostatrienoic                                                                 acid (Example                                                                  1373)                                                                  1471    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-16,16-dimethyl-                                           xy-16,16-di-   5-cis,10,13-trans-pro-                                          methyl-5-cis,13-                                                                              statrienoic acid                                                trans-prostadi-                                                                enoic acid (Exam-                                                              ple 1374)                                                              1472    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-16,16-dimethyl-                                           xy-16,16-di-   8-iso-5-cis,10,13-                                              methyl-8-iso-5-                                                                               trans-prostatrienoic                                            cis,13-trans-  acid                                                            prostadienoic                                                                  acid (Example                                                                  1374)                                                                  1473    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-16,16-dimethyl-                                           xy-16,16-di-   5-cis,10,13-cis-pro-                                            methyl-5-cis,13-                                                                              statrienoic acid                                                cis-prostadie-                                                                 noic acid (Exam-                                                               ple 1374)                                                              1474    8β-methyl-9-oxo-                                                                         8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-16,16-dimethyl-                                           xy-16,16-di    8-iso-5-cis,10,13-cis-                                          methyl-8-iso-5-                                                                               prostatrienoic acid                                             cis,13-cis-pro-                                                                stadienoic acid                                                                (Example 1374)                                                         1475    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4-nor-20-methyl-                                          xy-4-nor-20-   5-cis,10,13-trans-pro-                                          methyl-5-cis,- statrienoic acid                                                13-trans-prosta-                                                               dienoic acid                                                                   (Example 1375)                                                         1476    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α ,15-dihydro-                                                                        droxy-4-nor-20-methyl-                                          xy-4-nor-20-   8-iso-5-cis,10,13-                                              methyl-8-iso-  trans-prostatrienoic                                            5-cis,13-trans-                                                                               acid                                                            prostadienoic                                                                  acid (Example                                                                  1375)                                                                  1477    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4-nor-20-methyl-                                          xy-4-nor-20-   5-cis,10,13-cis-pro-                                            methyl-5-cis,- statrienoic acid                                                13-cis-prostadi-                                                               enoic acid                                                                     (Example 1375)                                                         1478    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4-nor-20-methyl-                                          xy-4-nor-20-   8-iso-5-cis,10,13-                                              methyl-8-iso-  cis-prostatrienoic                                              5-cis,13-cis-  acid                                                            prostadienoic                                                                  acid (Example                                                                  1375)                                                                  1479    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4a-homo-17,17-di-                                         xy-4a-homo-17,-                                                                               methyl-5-cis,10,13-                                             17-dimethyl-5- trans-prostatrienoic                                            cis,13-trans-  acid                                                            prostadienoic                                                                  acid (Example                                                                  1376)                                                                  1480    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a-homo-17,17-di-                                         (Example methyl-8-iso-5-cis,10-                                                17-dimethyl-8- 13-trans-prostatrienoic                                         iso-5-cis,13-  acid                                                            trans-prostadi-                                                                enoic acid (Exam-                                                              ple 1376)                                                              1481    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a-homo-17,17-di-                                         xy-4a-homo-17,-                                                                               methyl-5-cis,10,13-cis-                                         17-dimethyl-5-                                                         prostatrienoic acid                                                                    cis,13-cis-pro-                                                                stadienoic acid                                                                (Example 1376)                                                         1482    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a-homo-17,17-di-                                         xy-4a-homo-17,-                                                                               methyl-8-iso-5-cis,10-                                          17-dimethyl-8- 13-cis-prostatrienoic                                           iso-5-cis,13-  acid                                                            cis-prostadie-                                                                 noic acid (Exam-                                                               ple 1376)                                                              1483    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bis-  20-ethyl-5-cis,10,13-                                           homo-20-ethyl- trans-prostatrienoic                                            5-cis,13-trans-                                                                               acid                                                            prostadienoic                                                                  acid (Example                                                                  1377)                                                                  1484    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bis-  20-ethyl-8-iso-5-cis,-                                          homo-20-ethyl-8-                                                                              10,13-trans-prostatrie-                                         iso-5-cis,13-  noic acid                                                       trans-prostadi-                                                                enoic acid                                                                     (Example 1377)                                                         1485    8α-methyl-9-oxo-                                                                        8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bis-  20-ethyl-5-cis,10,13-                                           homo-20-ethyl-5-                                                                              cis-prostatrienoic                                              cis,13-cis-pro-                                                                               acid                                                            stadienoic acid                                                                (Example 1377)                                                         1486    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bishomo-                                                                             20-ethyl-8-iso-5-cis,-                                          20-ethyl-8-iso-                                                                               10,13-cis-prostatrie-                                           5-cis,13-cis-  noic acid                                                       prostadienoic                                                                  acid (Example                                                                  1377)                                                                  1487    8α-methyl-9-oxo-                                                                        8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bishomo-                                                                             5-cis-10,13-trans,17-                                           5-cis,13-trans,-                                                                              cis-prostatetraenoic                                            17-cis-prostatri-                                                      methyl-9α enoic acid                                                             (Example 1378)                                                         1488    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-                                            xy-4a,4b-bishomo-                                                                             8-iso-5-cis,10,13-                                              8-iso-5-cis,13-                                                                               trans,17-cis-prostate-                                          trans,17-cis-  traenoic acid                                                   prostatrienoic                                                                 acid (Example                                                                  1378)                                                                  1489    8β-methyl-9-oxo-                                                                         8β-methyl-9-oxo-15-hy-                                     11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-5-                                          xy-4a,4b-bishomo-                                                                             cis,10,13-cis-17-cis-                                           5-cis,13-cis-  prostatetraenoic acid                                           17-cis-prosta- acid                                                            trienoic acid                                                                  (Example 1378)                                                         1490    8α-methyl-9-oxo-                                                                        8α-methyl-9-oxo-15-hy-                                    11α,15-dihydro-                                                                         droxy-4a,4b-bishomo-8-                                          xy-4a,4b-bishomo-                                                                             iso-5-cis,10,13-cis-                                            8-iso-5-cis,13-                                                                               17-cis-prostatetrae-                                            cis-17-cis-pro-                                                                               noic acid                                                       statrienoic acid                                                               (Example 1378)                                                         1491    methyl 8β-methyl-                                                                        methyl 8β-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-20-methyl-                                           hydroxy-20-methyl-                                                                            10,13-trans-prostadi-                                           13-trans-proste-                                                                              enoate                                                          noate (Example                                                                 1379)                                                                  1492    methyl 8α-methyl-                                                                       methyl 8α-methyl-9-oxo-                                   9-oxo-11α,15-di-                                                                        15-hydroxy-20-methyl-                                           hydroxy-20-    8-iso-10,13-trans-pro-                                          methyl-8-iso-  stadienoate                                                     13-trans-pro-                                                                  stenoate (Exam-                                                                ple 1379)                                                              1493    methyl 8β-methyl-                                                                        methyl 8β-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-20-methyl-                                           hydroxy-20-    10,13-cis-prostadie-                                            methyl-13-cis- noate                                                           prostenoate                                                                    (Example 1379)                                                         1494    methyl 8α-methyl-                                                                       methyl 8α-methyl-9-oxo-                                   9-oxo-11α,15-di-                                                                        15-hydroxy-20-methyl-                                           hydroxy-20-    8-iso-10,13-cis-pro-                                            methyl-8-iso-  stadienoate                                                     13-cis-proste-                                                                 noate (Example                                                                 1379)                                                                  1495    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-7a,7b-bis-                                           tatrienoic homo-10,13-trans,17-                                                bishomo-13-    cis-prostatrienoate                                             trans,17-cis-                                                                  prostadienoate                                                                 (Example 1380)                                                         1496    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-7a,7b-bis-                                           hydroxy-7a,7b- homo-8-iso-10,13-trans,-                                        bishomo-8-iso- 17-cis-prostatrienoate                                          13-trans,17-                                                                   cis-prostadie-                                                                 noate (Example                                                                 1380)                                                                  1497    ethyl8β-methyl-                                                                          ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-                                                                           15-hydroxy-7a,7b-bis-                                           dihydroxy-7a,- homo-10,13-cis,17-cis-                                          7b-bishomo-13- prostatrienoate                                                 cis,17-cis-pro-                                                                stadienoate                                                                    (Example 1380)                                                         1498    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-7a,7b-bis-                                           hydroxy-7a,7b- homo-8-iso-10,13-cis,-                                          bishomo-8-iso- 17-cis-prostatrienoate                                          13-cis,17-cis-                                                                 prostadienoate                                                                 (Example 1380)                                                         1499    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-2-ethyl-                                             hydroxy-2-ethyl-                                                                              16,16-dimethyl-10,13-                                           16,16-dimethyl-                                                                               trans-prostadienoate                                            13-trans-proste-                                                               noate (Example                                                                 1381)                                                                  1500    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-2-ethyl-                                             hydroxy-2-ethyl-                                                                              16,16-dimethyl-8-iso-                                           16,16-dimethyl-                                                                               10,13-trans-prostadi-                                           8-iso-13-trans-                                                                               enoate                                                          prostenoate                                                                    (Example 1381)                                                         1501    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-2-ethyl-                                             hydroxy-2-ethyl-                                                                              16,16-dimethyl-10,13-                                           16,16-dimethyl-                                                                               cis-prostadienoate                                              13-cis-proste-                                                                 noate (Example                                                                 1381)                                                                  1502    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α b,11α-                                                                  hydroxy-2-ethyl- 16,16-dimethyl-8-iso-                          16,16-dimethyl-                                                                               10,13-cis-prostadie-                                            8-iso-13-cis-  noate                                                           prostenoate                                                                    (Example 1381)                                                         1503    ethyl 8α-methyl-                                                                        ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-3,3,17,17-                                           hydroxy-3,3,17,-                                                                              tetramethyl-10,13-                                              17-tetramethyl-                                                                               trans-prostadienoate                                            13-trans-proste-                                                               noate (Example                                                                 1382)                                                                  1504    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-3,3,17,17-                                           hydroxy-3,3,17,-                                                                              tetramethyl-8-iso-10,-                                          17-tetramethyl-8-                                                                             13-trans-prostadienoate                                         iso-13-trans-pro-                                                              stenoate (Example                                                              1382)                                                                  1505    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-3,3,17,17-                                           hydroxy-3,3,17,-                                                                              tetramethyl-10,13-cis-                                          17-tetramethyl-                                                                               prostadienoate                                                  13-cis-proste-                                                                 noate (Example                                                                 1382)                                                                  1506    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-3,3,17,17-                                           hydroxy-3,3,17,-                                                                              tetramethyl-8-iso-10,-                                          17-tetramethyl-                                                                               13-cis-prostadienoate                                           8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1382)                                                         1507    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-3-oxa-17,-                                           hydroxy-3-oxa- 17-dimethyl-10,13-trans-                                        17,17-dimethyl-                                                                               prostadienoate                                                  13-trans-proste-                                                               noate (Example                                                                 1383)                                                                  1508    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-3-oxa-17,17-                                         hydroxy-3-oxa- dimethyl-8-iso-10,13-                                           17,17-dimethyl-                                                                               trans-prostadienoate                                            8-iso-13-trans-                                                                prostenoate                                                                    (Example 1383)                                                         1509    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-3-oxa-17,17-                                         hydroxy-3-oxa- dimethyl-10,13-cis-                                             17,17-dimethyl-                                                                               prostadienoate                                                  13-cis-proste-                                                                 noate (Example                                                                 1383)                                                                  1510    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-3-oxa-17,-                                           hydroxy-3-oxa- 17-dimethyl-8-iso-10,-                                          17,17-dimethyl-                                                                               13-cis-prostadienoate                                           8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1383)                                                         1511    butyl 8β-methyl-                                                                         butyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-10,13-trans-                                         hydroxy-13-trans-                                                                             prostadienoate                                                  prostenoate                                                                    (Example 1384)                                                         1512    buty 8α-methyl-                                                                         butyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-8-iso-10,-                                           hydroxy-8-iso-13-                                                                             13-trans-prostadienoate                                         trans-prosteno-                                                                ate (Example                                                                   1384)                                                                  1513    butyl 8β-methyl-                                                                         butyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-13-cis-pro-                                          hydroxy-13-cis-                                                                               stadienoate                                                     prostenoate                                                                    (Example 1384)                                                         1514    butyl 8α-methyl-                                                                        butyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-8-iso-10,13-                                         hydroxy-8-iso-13-                                                                             cis-prostadienoate                                              cis-prostenoate                                                                (Example 1384)                                                         1515    decyl 8β-methyl-                                                                         decyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-10,13-trans,-                                        hydroxy-13-trans,-                                                                            17-cis-prostatrienoate                                          17-cis-prostadi-                                                               enoate (Example                                                                1385)                                                                  1516    decyl 8α-methyl-                                                                        decyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-8-iso-10,-                                           hydroxy-8-iso- 13-trans,17-cis-prosta-                                         13-trans,17-cis-                                                                              trienoate                                                       prostadienoate                                                                 (Example 1385)                                                         1517    decyl 8β-methyl-                                                                         decyl 8β-methyl-9-oxo-                                     9-oxo-11α,15-di-                                                                        15-hydroxy-10,13-cis-                                           hydroxy-13-cis-                                                                               17-cis-prostatrienoate                                          17-cis-prostadi-                                                               enoate (Example                                                                1385)                                                                  1518    decyl 8α-methyl-                                                                        decyl 8α-methyl-9-oxo-                                    9-oxo-11α,15-di-                                                                        15-hydroxy-8-iso-10,13-                                         hydroxy-8-iso-13-                                                                             cis-17-cis-prostatrie-                                          cis-17-cis-pro-                                                                               noate                                                           stadienoate                                                                    (Example 1385)                                                         1519    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α-ace-                                                                          15-hydroxy-10,13-trans-                                         toxy-15-hydroxy-                                                                              prostadienoate                                                  13-trans-proste-                                                               noate (Example                                                                 1386)                                                                  1520    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α-ace-                                                                          15-hydroxy-8-iso-10,13-                                         toxy-15-hydroxy-                                                                              trans-prostadienoate                                            8-iso-13-trans-                                                                prostenoate                                                                    (Example 1386)                                                         1521    ethyl 8β-methyl-                                                                         ethyl 8β-methyl-9-oxo-                                     9-oxo-11α-ace-                                                                          15-hydroxy-10,13-cis-                                           toxy-15-hydroxy-                                                                              prostadienoate                                                  13-cis-proste-                                                                 noate (Example                                                                 1386)                                                                  1522    ethyl 8α-methyl-                                                                        ethyl 8α-methyl-9-oxo-                                    9-oxo-11α-ace-                                                                          15-hydroxy-8-iso-10,13-                                         toxy-15-hydroxy-                                                                              cis-prostadienoate                                              8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1386)                                                         ______________________________________                                    

EXAMPLES 1523-1654

Treatment of the designated 9-oxo-prostenoic acid and ester derivatives listed in Table 42 below with sodium borohydride in ethanol as described in Example 257 gives the product 9α and 9β hydroxy derivatives of the table, which are separable by standard chromatographic techniques.

                  TABLE 42                                                         ______________________________________                                               Starting 8-     Product                                                        methyl-9-oxo-   8-methyl-9α/β,-                                     11α ,15-di-                                                                              11α,15-trihydroxy-                                 Ex-   hydroxy-13-prosten-                                                                            13-prostenoic                                            ample oic acid or ester                                                                              acid or ester                                            ______________________________________                                         1523  8β-methyl-prosta-                                                                         8β-methyl-prosta-                                         glandin E.sub.1 glandin F.sub.1 α/F.sub.1 β                         (Example 1353)                                                           1524  8α-methyl-8-iso-                                                                         8α-methyl-8-iso-pros-                                    prostaglandin E.sub.1                                                                          taglandin F.sub.1 α/F.sub.1 β                       (Example 1353)                                                           1525  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α,-                     15-dihydroxy-13-cis-                                                                           15-trihydroxy-13-                                              prostenoic acid cis-prostenoic acid                                            (Example 1353)                                                           1526  8α-methyl-9-oxo-                                                                         8α-methyl-9α/β,11α,                     11α,15-dihydroxy-                                                                        15-trihydroxy-8-iso-                                           8-iso-13-cis-pros-                                                                             13-cis-prostenoic                                              tenoic acid     acid                                                           (Example 1353)                                                           1527  8β-methyl-9-oxo-                                                                          8β-methyl-9α/β,11α,-                     11α,15-dihydroxy-                                                                        15-trihydroxy-16,16-                                           16,16-dimethyl-13-                                                                             dimethyl-13-trans-                                             trans-prostenoic                                                                               prostenoic acid                                                acid                                                                           (Example 1354)                                                           1528  8α-methyl-9-oxo-                                                                         8α-methyl-9α/β,11α,-                    11α,15-dihydroxy-                                                                        15-trihydroxy-16,16-                                           16,16-dimethyl-8-                                                                              dimethyl-8-iso-13-                                             iso-13-trans-pros-                                                                             trans-prostenoic acid                                          tenoic acid                                                                    (Example 1354)                                                           1529  8β-methyl-9-oxo-                                                                          8β-methyl-9α/β,11α-                      11α,15-dihydroxy-                                                                        15-trihydroxy-16,16-                                           16,16-dimethyl-13-                                                                             dimethyl-13-cis-                                               cis-prostenoic acid                                                                            prostenoic acid                                                (Example 1354)                                                           1530  8α-methyl-9-oxo-                                                                         8α-methyl-9α/β,11α,                     11α,15-dihydroxy-                                                                        15-trihydroxy-16,16-                                           16,16-dimethyl-8-                                                                              dimethyl-8-iso-13-                                             iso-13-cis-pros-                                                                               cis-prostenoic acid                                            tenoic acid                                                                    (Example 1354)                                                           1531  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α,-                     15-dihydroxy-17,17-                                                                            15-trihydroxy-17,17-                                           dimethyl-13-trans-                                                                             dimethyl-13-trans-                                             prostenoic acid prostenoic acid                                                (Example 1355)                                                           1532  8α-methyl-9-oxo-                                                                         8α-methyl-9α/β,11α,-                    11α,15-dihydroxy-8-                                                                      15-trihydroxy-17,17-                                           iso-17,17-di-   dimethyl-8-iso-13-                                             methyl-13-trans-                                                                               trans-prostenoic                                               prostenoic acid acid                                                           (Example 1355)                                                           1533  8β-methyl-9-oxo-                                                                          8β-methyl-9α/β,11α,-                     11α,15-dihydroxy-17,                                                                     15-trihydroxy-17,17-                                           17-dimethyl-13-cis-                                                                            dimethyl-13-cis-                                               prostenoic acid prostenoic acid                                                (Example 1355)                                                           1534  8α-methyl-9-oxo-                                                                         8α-methyl-9α/β,11α,-                    11α,15-dihydroxy-                                                                        15-trihydroxy-8-iso-                                           17,17-dimethyl-8-                                                                              17,17-dimethyl-13-                                             iso-13-cis-pros-                                                                               cis-prostenoic                                                 tenoic acid     acid                                                           (Example 1355)                                                           1535  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α-                      15-dihydroxy-13-                                                                               15-trihydroxy-13-                                              trans-17-cis-pro-                                                                              trans,17-cis-pros-                                             stadienoic acid tadienoic acid                                                 (Example 1356)                                                           1536  8α-methyl-9-oxo-11α-                                                               8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-trihydroxy-8-iso-                                           13-trans,17-cis-                                                                               13-trans-17-cis-                                               prostadienoic acid                                                                             prostadienoic acid                                             (Example 1356)                                                           1537  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α,-                     15-dihydroxy-13-cis,                                                                           15-trihydroxy-13-cis,                                          17-cis-prostadienoic                                                                           17-cis-prostadienoic                                           acid            acid                                                           (Example 1356)                                                           1538  8α-methyl-9-oxo-11α-                                                               8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-trihydroxy-8-iso-                                           13-trans-17-cis-                                                                               13-cis,17-cis-pros-                                            prostadienoic acid                                                                             tadienoic acid                                                 (Example 1356)                                                           1539  8β-methyl-9-oxo-11α-                                                                8β -methyl-9α/β,11α,-                    15-dihydroxy-20-                                                                               15-trihydroxy-20-                                              ethyl-13-trans-pros-                                                                           ethyl-13-trans-pros-                                           tenoic acid     tenoic acid                                                    (Example 1357)                                                           1540  8α-methyl-9-oxo-11α-                                                               8α-methyl-9α/β,11α,-                    15-dihydroxy-20-                                                                               15-trihydroxy-20-                                              ethyl-8-iso-13-trans-                                                                          ethyl-8-iso-13-                                                prostenoic acid trans-prostenoic                                               (Example 1357)  acid                                                     1541  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α,-                     15-dihydroxy-20-eth-                                                                           15-trihydroxy-20-                                              yl-13-cis-prostenoic                                                                           ethyl-13-cis-pro-                                              acid            stenoic acid                                                   (Example 1357)                                                           1542  8α-methyl-9-oxo-11α-                                                               8α-methyl-9α/β,11α,-                    15-dihydroxy-20-                                                                               15-trihydroxy-20-                                              ethyl-8-iso-13-cis-                                                                            ethyl-8-iso-13-cis-                                            prostenoic acid prostenoic acid                                                (Example 1357)                                                           1543  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-6,7-                                                                              15-trihydroxy-6,7-                                             dinor-13-trans-pros-                                                                           dinor-13-trans-pros-                                           tenoic acid     tenoic acid                                                    (Example 1358)                                                           1544  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-6,7-                                                                              15-trihydroxy-6,7-                                             dinor-8-iso-13-trans-                                                                          dinor-8-iso-13-                                                prostenoic acid trans-prostenoic                                               (Example 1358)  acid                                                     1545  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-6,7-                                                                              15-trihydroxy-6,7-                                             dinor-13-cis-   dinor-13-cis-                                                  prostenoic acid prostenoic acid                                                (Example 1358)                                                           1546  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-6,7-                                                                              15-trihydroxy-6,7-                                             dinor-8-iso-13-cis-                                                                            dinor-8-iso-13-cis-                                            prostenoic acid prostenoic acid                                                (Example 1358)                                                           1547  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-5,6,7-                                                                            15-trihydroxy-5,6,7-                                           trinor-20-methyl-13-                                                                           trinor-20-methyl-13-                                           trans-prostenoic acid                                                                          trans-prostenoic acid                                          (Example 1359)                                                           1548  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-5,6,7-                                                                            15-trihydroxy-5,6,7-                                           trinor-20-methyl-8-                                                                            trinor-20-methyl-8-                                            iso-13-trans-pros-                                                                             iso-13-trans-prosten-                                          tenoic acid     oic acid                                                       (Example 1359)                                                           1549  8β-methyl-9-oxo-11α-                                                                8β-methyl-9α/β,11α,-                     15-dihydroxy-5,6,7,-                                                                           15-trihydroxy-5,6,7-                                           trinor-20-methyl-                                                                              trinor-20-methyl-13-                                           13-cis-prostenoic                                                                              cis-prostenoic acid                                            acid                                                                           (Example 1359)                                                           1550  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-5,6,7-                                                                            15-trihydroxy-5,6,7-                                           trinor-20-methyl-8-                                                                            trinor-20-methyl-8-                                            iso-13-cis-prosten-                                                                            iso-13-cis-prosten-                                            oic acid        oic acid                                                       (Example 1359)                                                           1551  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-7a,7b-                                                                            15-trihydroxy-7a,7b-                                           bishomo-13-trans-                                                                              bishomo-13-trans-                                              prostenoic acid prostenoic acid                                                (Example 1360)                                                           1552  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7a,7b-                                                                            15-trihydroxy-7a,7b-                                           bishomo-8-iso-13-                                                                              bishomo-8-iso-13-                                              trans-prostenoic                                                                               trans prostenoic                                               acid            acid                                                           (Example 1360)                                                           1553  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,                      15-dihydroxy-7a,7b-                                                                            15-trihydroxy-7a,7b-                                           bishomo-13-cis- bishomo-13-cis-pro-                                            prostenoic acid stenoic acid                                                   (Example 1360)                                                           1554  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7a,7b-                                                                            15-trihydroxy-7a,7b-                                           bishomo-8-iso-13-                                                                              bishomo-8-iso-13-cis-                                          cis-prostenoic acid                                                                            prostenoic acid                                                (Example 1360)                                                           1555  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-eth-                                                                            15-trihydroxy-2-                                               yl-13-trans-prosten-                                                                           ethyl-13-trans-                                                oic acid        prostenoic acid                                                (Example 1361)                                                           1556  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β ,11α,-                   15-dihydroxy-2-eth-                                                                            15-trihydroxy-2-                                               yl-8-iso-13-trans-                                                                             ethyl-8-iso-13-trans-                                          prostenoic acid prostenoic acid                                                (Example 1361)                                                           1557  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-ethyl-                                                                          15-trihydroxy-2-                                               13-cis-prostenoic                                                                              ethyl-13-cis-pro-                                              acid            stenoic acid                                                   (Example 1361)                                                           1558  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α-                     15-dihydroxy-2- 15,trihydroxy-2-                                               ethyl-8-iso-13-cis-                                                                            ethyl-8-iso-13-cis-                                            prostenoic acid prostenoic acid                                                (Example 1361)                                                           1559  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3,3,20-                                                                           15-trihydroxy-3,3,20-                                          trimethyl-8-iso-13-                                                                            trimethyl-13-trans-                                            trans-prostenoic                                                                               prostenoic acid                                                acid (Example 1362)                                                      1560  8α-methyl-9-oxo-11α,-                                                              8β-methyl-9α/β,11α,-                     15-dihydroxy-3,3,20-                                                                           15-trihydroxy-3,3,                                             trimethyl-8-iso-13-                                                                            20-trimethyl-8-iso-                                            trans-prostenoic ac                                                                            13-trans-prostenoic                                            acid (Example 1362)                                                                            acid                                                     1561  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3,3,20-                                                                           15-trihydroxy-3,3,                                             trimethyl-13-cis-                                                                              20-trimethyl-13-cis-                                           prostenoic acid prostenoic acid                                                (Example 1362)                                                           1562  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-3,3,20-                                                                           15-trihydroxy-3,3,20-                                          trimethyl-8-iso-13-                                                                            trimethyl-8-iso-13-                                            cis-prostenoic acid                                                                            cis-prostenoic acid                                            (Example 1362)                                                           1563  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           13-trans-prostenoic                                                                            13-trans-prostenoic                                            acid            acid                                                           (Example 1363                                                            1564  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9-α/β ,11α,-                  15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           8-iso-13-trans- 8-iso-13-trans-                                                prostenoic acid prostenoic acid                                                (Example 1363)                                                           1565  8β-methyl-9-oxo-11α ,-                                                              8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-8                                                                           15-trihydroxy-3-oxa-                                           8-iso-13-cis-pro-                                                                              8-iso-13-cis-pro-                                              stenoic acid    stenoic acid                                                   (Example 1363)                                                           1566  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           8-iso-13-cis-pro-                                                                              8-iso-13-cis-pro-                                              stenoic acid    stenoic acid                                                   (Example 1363)                                                           1567  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β-11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           16,16-dimethyl-13-                                                                             16,16-dimethyl-13-                                             trans-prostenoic                                                                               trans-prostenoic                                               acid            acid                                                           (Example 1364)                                                           1568  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β-11α,-                    15-dihydroxy-3-oxa-                                                                            5-trihydroxy-3-oxa-                                            16,16-dimethyl-8-                                                                              16,16-dimethyl-8-                                              iso-13-trans-pro-                                                                              iso-13-trans-pro-                                              stenoic acid    stenoic acid                                                   (Example 1364)                                                           1569  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β-11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           16,16-dimethyl-13-                                                                             16,16-dimethyl-13-                                             cis-prostenoic acid                                                                            cis-prostenoic acid                                            (Example 1364)                                                           1570  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β-11α,-                    15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           16,16-dimethyl-8-                                                                              16,16-dimethyl-8-                                              iso-13-cis-pro- iso-13-cis-pro-                                                stenoic acid    stenoic acid                                                   (Example 1364)                                                           1571  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           13-trans,17-cis-                                                                               13-trans,17-cis-                                               prostadienoic acid                                                                             prostadienoic acid                                             (Example 1365)                                                           1572  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           8-iso-13-trans,17-                                                                             8-iso-13-trans,17-                                             cis-prostadienoic                                                                              cis-prostadienoic                                              acid            acid                                                           (Example 1365)                                                           1573  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           13-cis,17-cis-pro-                                                                             13-cis,17-cis-                                                 stadienoic acid prostadienoic acid                                             (Example 1365)                                                           1574  8α-methyl-9-oxo-11α,-                                                              8α-metyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           8-iso-13-cis,17-cis-                                                                           8-iso-13-cis,17-cis-                                           prostadienoic acid                                                                             prostadienoic acid                                             (Example 1365)                                                           1575  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           20-ethyl-13-trans-                                                                             20-ethyl-13-trans-                                             prostenoic acid prostenoic acid                                                (Example 1366)                                                           1576  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           20-ethyl-8-iso-13-                                                                             20-ethyl-8-iso-13-                                             trans-prostenoic                                                                               trans-prostenoic                                               acid            acid                                                           (Example 1366)                                                           1577  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           20-ethyl-13-cis-                                                                               20-ethyl-13-cis-                                               prostenoic acid prostenoic acid                                                (Example 1366)                                                           1578  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-3-oxa-                                                                            15-trihydroxy-3-oxa-                                           20-ethyl-8-iso-13-                                                                             20-ethyl-8-iso-13-                                             cis-prostenoic acid                                                                            cis-prostenoic acid                                            (Example 1366)                                                           1579  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-flu-                                                                            15-trihydroxy-2-                                               oro-17,17-dimethyl-                                                                            fluoro-17,17-dimeth-                                           13-trans-prostenoic                                                                            yl-13-trans-prosten-                                           acid            oic acid                                                       (Example 1367)                                                           1580  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-2-flu-                                                                            15-trihydroxy-2-                                               oro-17,17-dimethyl-                                                                            fluoro-17,17-dimeth-                                           8-iso-13-trans- yl-8-iso-13-trans-                                             prostenoic acid prostenoic acid                                                (Example 1367)                                                           1581  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2- 15-trihydroxy-2-                                               fluoro-17,17-di-                                                                               fluoro-17,17-dimeth-                                           methyl-13-cis-pros-                                                                            yl-13-cis-prostenoic                                           tenoic acid     acid                                                           (Example 1367)                                                           1582  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-2-flu-                                                                            15-trihydroxy-2-                                               oro-17,17-dimethyl-                                                                            fluoro-17,17-dimeth-                                           8-iso-13-cis-pros-                                                                             yl-8-iso-13-cis-                                               tenoic acid     prostenoic acid                                                (Example 1367)                                                           1583  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-7-nor-                                                                            15-trihydroxy-7-nor-                                           13-trans-prostenoic                                                                            13-trans-prostenoic                                            acid            acid                                                           (Example 1368)                                                           1584  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7-nor-                                                                            15-trihydroxy-7-nor-                                           8-iso-13-trans-pros-                                                                           8-iso-13-trans-pros-                                           tenoic acid     tenoic acid                                                    (Example 1368)                                                           1585  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-7-nor-                                                                            15-trihydroxy-7-nor-                                           13-cis-prostenoic                                                                              13-cis-prostenoic                                              acid            acid                                                           (Example 1368)                                                           1586  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7-nor-                                                                            15-trihydroxy-7-nor-                                           8-iso-13-cis-prosten-                                                                          8-iso-13-cis-pro-                                              oic acid        stenoic acid                                                   (Example 1368)                                                           1587  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-7a-homo-                                                                          15-trihydroxy-7a-                                              16,16-dimethyl-13-                                                                             homo-16,16-dimethyl-                                           trans-prostenoic                                                                               13-trans-prostenoic                                            acid            acid                                                           (Example 1369)                                                           1588  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7a-                                                                               15-trihydroxy-7a-                                              homo-16,16-dimethyl-                                                                           homo-16,16-dimethyl-                                           8-iso-13-trans-pros-                                                                           8-iso-13-trans-pro-                                            tenoic acid     stenoic acid                                                   (Example 1369)                                                           1589  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-7a-                                                                               15-trihydroxy-7a-                                              homo-16,16-dimethyl-                                                                           homo-16,16-dimethyl-                                           13-cis-prostenoic                                                                              13-cis-prostenoic                                              acid            acid                                                           (Example 1369)                                                           1590  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-7a-                                                                               15-trihydroxy-7a-                                              homo-16,16-dimethyl-                                                                           homo-16,16-dimethyl-                                           8-iso-13-cis-prosten-                                                                          8-iso-13-cis-pros-                                             oic acid        tenoic acid                                                    (Example 1369)                                                           1591  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-phen-                                                                           15-trihydroxy-2-                                               yl-13-trans-prosten-                                                                           phenyl-13-trans-pros-                                          oic acid        tenoic acid                                                    (Example 1370)                                                           1592  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-2-phen-                                                                           15-trihydroxy-2-phen-                                          yl-8-iso-13-trans-                                                                             yl-8-iso-13-trans-                                             prostenoic acid prostenoic acid                                                (Example 1370)                                                           1593  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-phen-                                                                           15-trihydroxy-2-phen-                                          yl-13-cis-prostenoic                                                                           yl-13-cis-prostenoic                                           acid            acid                                                           (Example 1370)                                                           1594  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-2-phen-                                                                           15-trihydroxy-2-                                               yl-8-iso-13-cis-                                                                               phenyl-8-iso-13-cis-                                           prostenoic acid prostenoic acid                                                (Example 1370)                                                           1595  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-meth-                                                                           15-trihydroxy-2-meth-                                          yl-13-trans-17-cis-                                                                            yl-13-trans,17-cis-                                            prostadienoic acid                                                                             prostadienoic acid                                             (Example 1371)                                                           1596  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α-                     15-dihydroxy-2- 15-trihydroxy-2-meth-                                          methyl-8-iso-13-                                                                               yl-8-iso-13-                                                   trans,17-cis-prosta-                                                                           cis-                                                           dienoic acid    acid                                                           (Example 1371)                                                           1597  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-2-meth-                                                                           15-trihydroxy-2-                                               yl-13-cis,17-cis-                                                                              methyl-13-cis,17-cis-                                          prostadienoic acid                                                                             prostadienoic acid                                             (Example 1371)                                                           1598  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-2- 15-trihydroxy-2-meth-                                          methyl-8-iso-13-cis,                                                                           yl-8-iso-13-cis,17-                                            17-cis-prostadienoic                                                                           cis-prostadienoic                                              acid (Example 1371)                                                                            acid                                                     1599  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-5,cis,-                                                                           15-trihydroxy-5 cis-                                           13-trans-prosta-                                                                               13-trans-prostadien-                                           dienoic acid    oic acid                                                       (Example 1372)                                                           1600  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-trihydroxy-8-iso-                                           5-cis-13-trans-pros-                                                                           5 cis,13-trans-pros-                                           tadienoic acid  tadienoic acid                                                 (Example 1372)                                                           1601  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-5-cis,                                                                            15-trihydroxy-5 cis-                                           13-cis-prostadien-                                                                             13-cis-prostadienoic                                           oic acid        acid                                                           (Example 1372)                                                           1602  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-trihydroxy-8-iso-                                           5-cis-13-cis-prosta-                                                                           5 cis 13-cis-prosta-                                           dienoic acid    dienoic acid                                                   (Example 1372)                                                           1603  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-5-cis,-                                                                           15-trihydroxy-5-cis,-                                          13-trans,17-cis-                                                                               13-trans,17-cis-                                               prostadienoic acid                                                             (Example 1373)                                                           1604  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-dihydroxy-8-iso-                                            5-cis,13-trans,17-                                                                             5-cis,13-trans,17-                                             cis-prostatrienoic                                                                             cis-prostatrienoic                                             acid            acid                                                           (Example 1373)                                                           1605  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-5-cis,-                                                                           15-trihydroxy-5-cis,-                                          13-cis,17-cis-prosta-                                                                          13-cis,17-cis-                                                 trienoic acid   prostatrienoic acid                                            (Example 1373)                                                           1606  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-8-iso-                                                                            15-trihydroxy-8-iso-                                           15-cis,13-cis,17-                                                                              5-cis,13-cis,17-cis-                                           cis-prostatrienoic                                                                             prostatrienoic acid                                            acid                                                                           (Example 1373)                                                           1607  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-16,16-                                                                            15-trihydroxy-16,16-                                           dimethyl-5-cis,13-                                                                             dimethyl-5-cis,13-                                             trans-prostadienoic                                                                            trans-prostadienoic                                            (Example 1374)  acid                                                     1608  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-16,16-                                                                            15-trihydroxy-16,16-                                           dimethyl-8-iso-5-                                                                              dimethyl-8-iso-5-cis-                                          cis,13-trans-prosta-                                                                           13-trans-prostadien-                                           dienoic acid    oic acid                                                       (Example 1374)                                                           1609  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-16,16-                                                                            15-trihydroxy-16,16-                                           dimethyl-5-cis  dimethyl-5-cis,13-                                             13-cis-prostadienoic                                                                           cis-prostadienoic                                              acid            acid                                                           (Example 1374)                                                           1610  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-16,16-                                                                            15-trihydroxy-16,16-                                           dimethyl-8-iso-5-cis-                                                                          dimethyl-8-iso-5-cis-                                          13-cis-prostadienoic                                                                           13-cis-prostadienoic                                           acid (Example 1374)                                                                            acid                                                     1611  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4-nor-                                                                            15-trihydroxy-4-nor-                                           20-methyl-5-cis,13-                                                                            20-methyl-5-cis,13-                                            trans-prostadienoic                                                                            trans-prostadienoic                                            acid            acid                                                           (Example 1375)                                                           1612  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4-nor-                                                                            15-trihydroxy-4-nor-                                           20-methyl-8-iso-5-                                                                             20-methyl-8-iso-                                               cis,13-trans-pros-                                                                             5-cis,13-trans-                                                tadienoic acid  prostadienoic acid                                             (Example 1375)                                                           1613  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4-nor-                                                                            15-trihydroxy-4-nor-                                           20-methyl-5-cis,13-                                                                            20-methyl-5-cis,13-                                            cis-prostadienoic                                                                              cis-prostadienoic                                              acid            acid                                                           (Example 1375)                                                           1614  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4-nor-                                                                            15-trihydroxy-4-nor-                                           20-methyl-8-iso-5-                                                                             20-methyl-8-iso-5-                                             cis,13-cis-prosta-                                                                             cis,13-cis-prosta-                                             dienoic acid    dienoic acid                                                   (Example 1375)                                                           1615  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4a-homo-                                                                          15-trihydroxy-4a-                                              17,17-dimethyl-5-cis-                                                                          homo-17,17-dimethyl-                                           13-trans-prostadien-                                                                           5-cis,13-trans-pros-                                           oic acid        tadienoic acid                                                 (Example 1376)                                                           1616  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a-homo-                                                                          15-trihydroxy-4a-                                              17,17-dimethyl-8-                                                                              homo-17,17-dimethyl-                                           iso-5-cis,13-trans-                                                                            8-iso-5-cis,13-cis-                                            prostadienoic acid                                                                             prostadienoic acid                                             (Example 1376)                                                           1617  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4a-homo-                                                                          15-trihydroxy-4a-                                              17,17-dimethyl-5-cis-                                                                          homo-17,17-dimethyl-                                           13-cis-prostadienoic                                                                           5-cis,13-cis-prosta-                                           acid            dienoic acid                                                   (Example 1376)                                                           1618  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a-homo-                                                                          15-trihydroxy-4a-                                              17,17-dimethyl-8-iso-                                                                          homo-17,17-dimethyl-                                           5-cis,13-cis-prosta-                                                                           8-iso-5-cis,13-cis-                                            dienoic acid    prostadienoic acid                                             (Example 1376)                                                           1619  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α /β,11α,-                    15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bishomo-20-ethyl-5-                                                                            bishomo-20-ethyl-                                              cis,13-trans-prosta-                                                                           5-cis,13-trans-pros-                                           dienoic acid    tadienoic acid                                                 (Example 1377)                                                           1620  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bishomo-20-ethyl-8-                                                                            bishomo-20-ethyl-8-                                            iso-5-cis,13-trans-                                                                            iso-5-cis,13-trans-                                            prostadienoic acid                                                                             prostadienoic acid                                             (Example 1377)                                                           1621  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bishomo-20-ethyl-5-                                                                            bishomo-20-ethyl-5-                                            cis,13-cis-prosta-                                                                             cis,13-cis-prosta-                                             dienoic acid    dienoic acid                                                   (Example 1377)                                                           1622  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bishomo-20-ethyl-8-                                                                            bishomo-20-ethyl-8-                                            iso-5-cis,13-cis-                                                                              iso-5-cis,13-cis-                                              prostadienoic acid                                                                             prostadienoic                                                  (Example 1377)                                                           1623  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bis-homo-5-cis,13-                                                                             bishomo-5-cis,13-                                              trans,17-cis-prosta-                                                                           trans,17-cis-prosta-                                           trienoic acid   trienoic acid                                                  (Example 1378)                                                           1624  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bis-homo-8-iso-5-cis-                                                                          bis-homo-8-iso-5-cis,-                                         13-trans,17-cis-pros-                                                                          13-trans,17-cis-                                               tatrienoic acid prostatrienoic acid                                            (Example 1378)                                                           1625  8β-methyl-9-oxo-11α,-                                                               8β-methyl-9α/β,11α,-                     15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bis-homo-5-cis,13-                                                                             bis-homo-5-cis,13-                                             cis,17-cis-pros-                                                                               cis-17-cis-prosta-                                             tatrienoic acid trienoic acid                                                  (Example 1378)                                                           1626  8α-methyl-9-oxo-11α,-                                                              8α-methyl-9α/β,11α,-                    15-dihydroxy-4a,4b-                                                                            15-trihydroxy-4a,4b-                                           bis-homo-8-iso-5-cis,                                                                          bis-homo-8-iso-5-                                              13-cis-17-cis-pros-                                                                            cis,13-cis,17-cis-                                             tatrienoic acid prostatrienoic acid                                            (Example 1378)                                                           1627  methyl 8β-methyl-9-                                                                       methyl 8β-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              20-methyl-13-trans-                                                                            hydroxy-20-methyl-                                             prostenoate     13-trans-prostenoate                                           (Example 1379)                                                           1628  methyl 8α-methyl-9-                                                                      methyl 8α-methyl-                                        oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              20-methyl-8-iso-13-                                                                            hydroxy-20-methyl-                                             trans-prostenoate                                                                              8-iso-13-trans-pros-                                           (Example 1379)  tenoate                                                  1629  methyl 8β-methyl-9-                                                                       methyl 8β-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              20-methyl-13-cis-                                                                              hydroxy-20-methyl-                                             prostenoate     13-cis-prostenoate                                             (Example 1379)                                                           1630  methyl 8α-methyl-9-                                                                      methyl 8α-methyl-                                        oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              20-methyl-8-iso-13-                                                                            hydroxy-20-methyl-                                             cis-prostenoate 8-iso-13-cis-pros-                                             (Example 1379)  tenoate                                                  1631  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α ,15-tri-                             7a,7b-bis-homo-13-                                                                             hydroxy-7a,7b-bis-                                             trans,17-cis-prosta-                                                                           homo-13-trans,17-                                              dienoate        cis-prostadienoate                                             (Example 1380)                                                           1632  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-9α/-                               oxo-11α,15-dihydroxy-                                                                    β,11α,15-trihydroxy-                                7a,7b-bis-homo-8-iso-                                                                          7a,7b-bis-homo-8-                                              13-trans,17-cis-                                                                               iso-13-trans,17-cis-                                           prostadienoate  prostadienoate                                                 (Example 1380)                                                           1633  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α b,11α,15-tri-                                   7a,7b-bis-homo-13-                                                                             hydroxy-7a,7b-bis-                                             cis-17-cis-prosta-                                                                             homo-13-cis,17-cis-                                            dienoate        prostadienoate                                                 (Example 1380)                                                           1634  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              7a,7b-bis-homo-8-                                                                              hydroxy-7a,7b-bis-                                             iso-13-cis,17-cis-                                                                             homo-8-iso-13-cis-                                             prostadienoate  17-cis-prosta-                                                 (Example 1380)  dienoate                                                 1635  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              2-ethyl-16,16-dimeth-                                                                          hydroxy-2-ethyl-16,                                            yl-13-trans-prosten-                                                                           16-dimethyl-13-                                                oate            trans-prostenoate                                              (Example 1381)                                                           1636  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              2-ethyl-16,16-di-                                                                              hydroxy-2-ethyl-                                               methyl-8-iso-13-                                                                               16,16-dimethyl-8-                                              trans-prostenoate                                                                              iso-13-trans-pros-                                             (Example 1381)  tenoate                                                  1637  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              2-ethyl-16,16-di-                                                                              hydroxy-2-ethyl-                                               methyl-13-cis-pros-                                                                            16,16-dimethyl-13-                                             tenoate         cis-prostenoate                                                (Example 1381)                                                           1638  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              2-ethyl-16,16-di-                                                                              hydroxy-2-ethyl-16,-                                           methyl-8-iso-13-cis-                                                                           16-dimethyl-8-iso-                                             prostenoate     13-cis-prostenoate                                             (Example 1381)                                                           1639  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3,3,17,17-tetra-                                                                               hydroxy-3,3,17,17-                                             methyl-13-trans-                                                                               tetramethyl-13-                                                prostenoate     trans-prostenoate                                              (Example 1382)                                                           1640  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3,3,17,17-tetra-                                                                               hydroxy-3,3,17,17-                                             methyl-8-iso-13-                                                                               tetramethyl-8-iso-                                             trans-prostenoate                                                                              13-trans-prosten-                                              (Example 1382)  oate                                                     1641  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3,3,17,17-tetramethyl-                                                                         hydroxy-3,3,17,17-                                             13-cis-prostenoate                                                                             tetramethyl-13-cis-                                            (Example 1382)  prostenoate                                              1642  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3,3,17,17-tetramethyl-                                                                         hydroxy-3,3,17,17-                                             8-iso-13-cis-prosten-                                                                          tetramethyl-8-iso-                                             oate            13-cis-prostenoate                                             (Example 1382)                                                           1643  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3-oxa-17,17-dimethyl-                                                                          hydroxy-3-oxa-17,17-                                           13-trans-prostenoate                                                                           dimethyl-13-trans-                                             (Example 1383)  prostenoate                                              1644  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3-oxa-17,17-dimethyl-                                                                          hydroxy-3-oxa-17,17-                                           8-iso-13-trans-pros-                                                                           dimethyl-8-iso-13-                                             tenoate         trans-prostenoate                                              (Example 1383)                                                           1645  ethyl 8β-methyl-9-                                                                        ethyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3-oxa-17,17-dimethyl-                                                                          hydroxy-3-oxa-17,17-                                           13-cis-prostenoate                                                                             dimethyl-13-cis-                                               (Example 1383)  prostenoate                                              1646  ethyl 8α-methyl-9-                                                                       ethyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              3-oxa-17,17-dimethyl-                                                                          hydroxy-3-oxa-17,17-                                           8-iso-13-cis-pros-                                                                             dimethyl-8-iso-13-                                             tenoate         cis-prostenoate                                                (Example 1383)                                                           1647  butyl 8β-methyl-9-                                                                        butyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              13-trans-prostenoate                                                                           hydroxy-13-trans-                                              (Example 1384)  prostenoate                                              1648  butyl 8α-methyl-9-                                                                       butyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              8-iso-13-trans- hydroxy-8-iso-13-                                              prostenoate     trans-prostenoate                                              (Example 1384)                                                           1649  butyl 8β-methyl-9-                                                                        butyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              13-cis-prostenoate                                                                             hydroxy-13-cis-                                                (Example 1384)  prostenoate                                              1650  butyl 8α-methyl-9-                                                                       butyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              8-iso-13-cis-pros-                                                                             hydroxy-8-iso-13-                                              tenoate         cis-prostenoate                                                (Example 1384)                                                           1651  decyl 8β-methyl-9-                                                                        decyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              13-trans,17-cis-                                                                               hydroxy-13-trans,-                                             prostadienoate  17-cis-prosta-                                                 (Example 1385)  dienoate                                                 1652  decyl 8α-methyl-9-                                                                       decyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              8-iso-13-trans,17-                                                                             hydroxy-8-iso-13-                                              cis-prostadienoate                                                                             trans,17-cis-pro-                                              (Example 1385)  stadienoate                                              1653  decyl 8β-methyl-9-                                                                        decyl 8β-methyl-                                          oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              13-cis,17-cis-pros-                                                                            hydroxy-13-cis,17-                                             tadienoate      cis-prostadienoate                                             (Example 1385)                                                           1654  decyl 8α-methyl-9-                                                                       decyl 8α-methyl-                                         oxo-11α,15-dihydroxy-                                                                    9α/β,11α,15-tri-                              8-iso-13-cis,17-cis-                                                                           hydroxy-8-iso-13-                                              prostadienoate  cis,17-cis-prosta-                                             (Example 1385)  dienoate                                                 ______________________________________                                    

EXAMPLES 1655-1781

Saponification of the alkyl esters designated in Table 43 below by the procedure described in Example 495 is productive of the carboxylic acids of the table. The epimeric 9α and 9β hydroxy products are separable by the usual chromatographic procedures.

                  TABLE 43                                                         ______________________________________                                         Ex-     Starting alkyl                                                         ample   prostenoate   Product prostenoic acid                                  ______________________________________                                         1655    11-deoxy-8β-meth-                                                                       11-deoxy-8β-methyl-pros-                                    yl-prostaglandin                                                                             taglandin E.sub.1                                                E.sub.1 methyl ester                                                           (Example 1188)                                                         1656    11-deoxy-8α-meth-                                                                      11-deoxy-8α-methyl-8-                                      yl-8-iso-prosta-                                                                             iso-prostaglandin E.sub.1                                        glandin E.sub.1 meth-                                                          yl ester (Exam-                                                                ple 1188)                                                              1657    methyl 15-hy- 15-hydroxy-8β-methyl-9-                                     droxy-8β-methyl                                                                         oxo-13-cis-prostenoic                                            9-oxo-13-cis- acid                                                             prostenoate                                                                    (Example 1188)                                                         1658    methyl-15-hy- 15-hydroxy-8α-methyl-8-                                    droxy-8α-methyl-                                                                       iso-9-oxo-13-cis-                                                8-iso-9-oxo-13-                                                                              prostenoic acid                                                  cis-prostenoate                                                                (Example 1188)                                                         1659    11-deoxy-8β-meth-                                                                       11-deoxy-8β-methyl-                                         yl-prostaglandin                                                                             prostaglandin F.sub.1 α/β                             F.sub.1 α/β methyl                                                  esters (Ex. 1206)                                                      1660    11-deoxy-8α-meth-                                                                      11-deoxy-8α-methyl-8-                                      yl-8-iso-prosta-                                                                             iso-prostaglandin                                                glandin F.sub.1 α/β                                                               F.sub.1 α/β                                           methyl esters                                                                  (Example 1207)                                                         1661    methyl 9α,15-di-                                                                       9α,15-dihydroxy-8β-meth-                              hydroxy-8β-meth-                                                                        yl-13-cis-prostenoic                                             yl-13-cis-pros-                                                                              acid                                                             tenoate (Example                                                               1208)                                                                  1662    ethyl 8β-methyl-                                                                        8β -methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-16,16-dimethyl-13-                                         droxy-16,16-di-                                                                              trans-prostenoic acid                                            methyl-13-trans-                                                               prostenoate                                                                    (Example 1190)                                                         1663    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-16,16-dimethyl-8-                                          droxy-16,16-di-                                                                              iso-13-trans-prosten-                                            methyl-8-iso-13-                                                                             oic acid                                                         trans-prosteno-                                                                ate (Example                                                                   1190)                                                                  1664    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-16,16-dimethyl-                                            droxy-16,16-di-                                                                              13-cis-prostenoic acid                                           methyl-13-cis-                                                                 prostenoate                                                                    (Example 1190)                                                         1665    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-16,16-dimethyl-                                            droxy-16,16-di-                                                                              8-iso-13-cis-prosten-                                            methyl-8-iso-13-                                                                             oic acid                                                         cis-prostenoate                                                                (Example 1190)                                                         1666    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-17,17-dimethyl-                                            droxy-17,17-di-                                                                              13-trans-prostenoic                                              methyl-13-trans-                                                                             acid                                                             prostenoate                                                                    (Example 1191)                                                         1667    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-17,17-dimethyl-                                            droxy-17,17-di-                                                                              8-iso-13-trans-pros-                                             methyl-8-iso-13-                                                                             tenoic acid                                                      trans-prosteno-                                                                ate (Example                                                                   1191)                                                                  1668    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-17,17-dimethyl-                                            droxy-17,17-di-                                                                              13-cis-prostenoic acid                                           methyl-13-cis-                                                                 prostenoate                                                                    (Example 1191)                                                         1669    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-17,17-dimethyl-8-                                          droxy-17,17-di-                                                                              iso-13-cis-prostenoic                                            methyl-8-iso-13-                                                                             acid                                                             cis-prostenoate                                                                (Example 1191)                                                         1670    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-13-trans,17-cis-                                           droxy-13-trans,-                                                                             prostadienoic acid                                               17-cis-prostadi-                                                               enoate (Example                                                                1192)                                                                  1671    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-13-trans,17-                                         droxy-8-iso-13-                                                                              cis-prostadienoic acid                                           trans,17-cis-                                                                  prostadienoate                                                                 (Example 1192)                                                         1672    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-13-cis,17-cis-                                             droxy-13-cis,17-                                                                             prostadienoic acid                                               cis-prostadien-                                                                oate (Example                                                                  1192)                                                                  1673    ethyl 8αmethyl-                                                                        8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-13-cis,17-                                           droxy-8-iso-13-                                                                              cis-prostadienoic acid                                           cis,17-cis-pros-                                                               tadienoate (Ex-                                                                ample 1192)                                                            1674    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-20-ethyl-13-trans-                                         droxy-20-ethyl-                                                                              prostenoic acid                                                  13-trans-pros-                                                                 tenoate (Example                                                               1193)                                                                  1675    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-20-ethyl-8-iso-13-                                         droxy-20-ethyl-                                                                              trans-prostenoic acid                                            8-iso-13-trans-                                                                prostenoate                                                                    (Example 1193)                                                         1676    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-20-ethyl-13-cis-                                           droxy-20-ethyl-                                                                              prostenoic acid                                                  13-cis-prosten-                                                                oate (Example                                                                  1193)                                                                  1677    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-20-ethyl-8-iso-13-                                         droxy-20-ethyl-                                                                              cis-prostenoic acid                                              8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1193)                                                         1678    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-7a,7b-bishomo-13-                                          droxy-7a,7b-bis-                                                                             trans-prostenoic acid                                            homo-13-trans-                                                                 prostenoate                                                                    (Example 1195)                                                         1679    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-7a,7b-bishomo-8-                                           droxy-7a,7b-bis-                                                                             iso-13-trans-prostenoic                                          homo-8-iso-13-                                                                               acid                                                             trans-prosteno-                                                                ate (Example                                                                   1195)                                                                  1680    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-7a,7b-bishomo-13-                                          droxy-7a,7b-bis-                                                                             cis-prostenoic acid                                              homo-13-cis-                                                                   prostenoate                                                                    (Example 1195)                                                         1681    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-7a,7b-bishomo-8-                                           droxy-7a,7b-bis-                                                                             iso-13-cis-prostenoic                                            homo-8-iso-13-                                                                               acid                                                             cis-prostenoate                                                                (Example 1195)                                                         1682    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2,20-bisethyl-13-                                          droxy-2,20-bis-                                                                              trans-prostenoic acid                                            ethyl-13-trans-                                                                prostenoate                                                                    (Example 1196)                                                         1683    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2,20-bisethyl-8-                                           droxy-2,20-bis-                                                                              iso-13-trans-prostenoic                                          ethyl-8-iso-13-                                                                              acid                                                             trans-prosten-                                                                 oate (Example                                                                  1196)                                                                  1684    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2,20-bisethyl-13-                                          droxy-2,20-bis-                                                                              cis-prostenoic acid                                              ethyl-13-cis-                                                                  prostenoate                                                                    (Example 1196)                                                         1685    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2,20-bisethyl-8-                                           droxy-2,20-bis-                                                                              iso-13-cis-prostenoic                                            ethyl-8-iso-13-                                                                              acid                                                             cis-prostenoate                                                                (Example 1196)                                                         1686    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-3-oxa-16,16-di-                                            droxy-3-oxa-16,-                                                                             methyl-13-trans-pros-                                            16-dimethyl-13-                                                                              tenoic acid                                                      trans-prosteno-                                                                ate (Example                                                                   1197)                                                                  1687    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-3-oxa-16,16-di-                                            droxy-3-oxa-16,-                                                                             methyl-8-iso-13-trans-                                           16-dimethyl-8-                                                                               prostenoic acid                                                  iso-13-trans-                                                                  prostenoate                                                                    (Example 1197)                                                         1688    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-3-oxa-16,16-di-                                            droxy-3-oxa-16,-                                                                             methyl-13-cis-prostenoic                                         16-dimethyl-13-                                                                              acid                                                             cis-prostenoate                                                                (Example 1197)                                                         1689    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-3-oxa-16,16-di-                                            droxy-3-oxa-16,-                                                                             methyl-8-iso-13-cis-                                             16-dimethyl-8-iso-                                                                           prostenoic acid                                                  13-cis-prosteno-                                                               ate (Example 1197)                                                     1690    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-3-oxa-13-trans,-                                           droxy-3-oxa-13-                                                                              17-cis-prostadienoic                                             trans,17-cis- acid                                                             prostadienoate                                                                 (Example 1198)                                                         1691    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-3-oxa-8-iso-13-                                            droxy-3-oxa-8-                                                                               trans,17-cis-prostadi-                                           iso-13-trans,17-                                                                             enoic acid                                                       cis-prostadieno-                                                               ate (Example                                                                   1198)                                                                  1692    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-3-oxa-13-cis,17-                                           droxy-3-oxa-13-                                                                              cis-prostadienoic acid                                           cis,17-cis-pros-                                                               tadienoate (Exam-                                                              ple 1198)                                                              1693    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-3-oxa-8-iso-13-                                            droxy-3-oxa-8-                                                                               cis,17-cis-prostadi-                                             iso-13-cis,17-                                                                               enoic acid                                                       cis-prostadieno-                                                               ate (Example                                                                   1198)                                                                  1694    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-7-nor-20-methyl-                                           droxy-7-nor-20-                                                                              13-trans-prostenoic                                              methyl-13-trans-                                                                             acid                                                             prostenoate                                                                    (Example 1199)                                                         1695    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-7-nor-20-methyl-                                           droxy-7-nor-20-                                                                              8-iso-13-trans-pros-                                             methyl-8-iso- tenoic acid                                                      13-trans-pros-                                                                 tenoate (Example                                                               1199)                                                                  1696    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-7-nor-20-methyl-                                           droxy-7-nor-20-                                                                              13-cis-prostenoic acid                                           methyl-13-cis-                                                                 prostenoate                                                                    (Example 1199)                                                         1697    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-7-nor-20-methyl-                                           droxy-7-nor-20-                                                                              8-iso-13-cis-prosteno-                                           methyl-8-iso- ic acid                                                          13-cis-prosten-                                                                oate (Example                                                                  1199)                                                                  1698    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2-fluoro-17,17-di-                                         droxy-2-fluoro-                                                                              methyl-13-trans-pros-                                            17,17-dimethyl-                                                                              tenoic acid                                                      13-trans-pros-                                                                 tenoate (Example                                                               1200)                                                                  1699    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2-fluoro-17,17-                                            droxy-2-fluoro-                                                                              dimethyl-8-iso-13-                                               17,17-dimethyl-                                                                              trans-prostenoic acid                                            8-iso-13-trans-                                                                prostenoate                                                                    (Example 1200)                                                         1700    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2-fluoro-17,17-                                            droxy-2-fluoro-                                                                              dimethyl-13-cis-                                                 17,17-dimethyl-                                                                              prostenoic acid                                                  13-cis-prosten-                                                                oate (Example                                                                  1200)                                                                  1701    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2-fluoro-17,17-                                            droxy-2-fluoro-                                                                              dimethyl-8-iso-13-cis-                                           17,17-dimethyl-                                                                              prostenoic acid                                                  8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1200)                                                         1702    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-10a-homo-13-                                               droxy-10a-homo-                                                                              trans-prostenoic acid                                            13-trans-pros-                                                                 tenoate (Example                                                               1201)                                                                  1703    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-10a-homo-8-iso-                                            droxy-10a-homo-8-                                                                            13-trans-prostenoic                                              iso-13-trans- acid                                                             prostenoate                                                                    (Example 1201)                                                         1704    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-10a-homo-13-cis-                                           droxy-10a-homo-                                                                              prostenoic acid                                                  13-cis-prosten-                                                                oate (Example                                                                  1201)                                                                  1705    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-10a-homo-8-iso-                                            droxy-10a-homo                                                                               13-cis-prostenoic acid                                           8-iso-13-cis-                                                                  prostenoate                                                                    (Example 1201)                                                         1706    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2-phenyl-20-meth-                                          droxy-2-phenyl-                                                                              yl-13-trans-prostenoic                                           20-methyl-13- acid                                                             trans-prosteno-                                                                ate (Example                                                                   1202)                                                                  1707    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2-phenyl-20-meth-                                          droxy-2-phenyl-                                                                              yl-8-iso-13-trans-pros-                                          20-methyl-8-iso-                                                                             tenoic acid                                                      13-trans-pros-                                                                 tenoate (Example                                                               1202)                                                                  1708    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-2-phenyl-20-meth-                                          droxy-2-phenyl-                                                                              yl-13-cis-prostenoic                                             20-methyl-13- acid                                                             cis-prostenoate                                                                (Example 1202)                                                         1709    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-2-phenyl-20-meth-                                          droxy-2-phenyl-                                                                              yl-8-iso-13-cis-prosten-                                         20-methyl-8-iso-                                                                             oic acid                                                         13-cis-prosten-                                                                oate (Example                                                                  1202)                                                                  1710    methyl 8β-methyl-                                                                       8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-5-cis,13-trans,17-                                         droxy-5-cis,13-                                                                              cis-prostatrienoic acid                                          trans,17-cis-                                                                  prostatrienoate                                                                (Example 1203)                                                         1711    methyl 8α-methyl-                                                                      8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-5-cis,13-                                            droxy-8-iso-5-                                                                               trans,17-cis-prostatri-                                          cis,13-trans,17-                                                                             enoic acid                                                       cis-prostatrien-                                                               oate (Example                                                                  1203)                                                                  1712    methyl 8β-methyl-                                                                       8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-5-cis,13-cis,17-                                           droxy-5-cis,13-                                                                              cis-prostatrienoic acid                                          cis,17-cis-pros-                                                               tatrienoate                                                                    (Example 1203)                                                         1713    methyl 8α-methyl-                                                                      8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-5-cis,13-                                            droxy-8-iso-5-                                                                               cis,17-cis-prostatri-                                            cis,13-cis,17-                                                                               enoic acid                                                       cis-prostatrien-                                                               oate (Example                                                                  1203)                                                                  1714    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-5-cis,13-trans-                                            droxy-5-cis,13-                                                                              prostadienoic acid                                               trans-prostadi-                                                                enoate (Example                                                                1204)                                                                  1715    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-5-cis,13-                                            droxy-8-iso-5-                                                                               trans-prostadienoic                                              cis,13-trans- acid                                                             prostadienoate                                                                 (Example 1204)                                                         1716    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-5-cis,13-cis-                                              droxy-5-cis,13-                                                                              prostadienoic acid                                               cis-prostadieno-                                                               ate (Example                                                                   1204)                                                                  1717    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-8-iso-5-cis,13-                                            droxy-8-iso-5-                                                                               cis-prostadienoic acid                                           cis,13-cis-pros-                                                               tadienoate (Exam-                                                              ple 1204)                                                              1718    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-20-ethyl-5-cis,13-                                         droxy-20-ethyl-                                                                              trans-prostadienoic acid                                         5-cis,13-trans-                                                                prostadienoate                                                                 (Example 1205)                                                         1719    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-20-ethyl-8-iso-5-                                          droxy-20-ethyl-                                                                              cis,13-trans-prostadi-                                           8-iso-5-cis,13-                                                                              enoic acid                                                       trans-prostadi-                                                                enoate (Example                                                                1205)                                                                  1720    ethyl 8β-methyl-                                                                        8β-methyl-9-oxo-15-hy-                                      9-oxo-15-hy-  droxy-20-ethyl-5-cis,13-                                         droxy-20-ethyl-                                                                              cis-prostadienoic acid                                           5-cis,13-cis-                                                                  prostadienoate                                                                 (Example 1205)                                                         1721    ethyl 8α-methyl-                                                                       8α-methyl-9-oxo-15-hy-                                     9-oxo-15-hy-  droxy-20-ethyl-8-iso-                                            droxy-20-ethyl-                                                                              5-cis,13-cis-prosta-                                             8-iso-5-cis,13-                                                                              dienoic acid                                                     cis-prostadien-                                                                oate (Example                                                                  1205)                                                                  1722    1210          8β-methyl-9α/β,15-dihy-                                        droxy-16,16-dimethyl-13-                                                       trans-prostenoic acid                                    1723    1211          8α-methyl-9α/β,15-di-                                         hydroxy-16,16-dimethyl-                                                        8-iso-13-trans-pros-                                                           tenoic acid                                              1724    1212          8β-methyl-9α/β,15-dihy-                                        droxy-16,16-dimethyl-13-                                                       cis-prostenoic acid                                      1725    1213          8α-methyl-9α/β,15-dihy-                                       hydroxy-16,16-dimethyl-                                                        8-iso-13-cis-prostenoic                                                        acid                                                     1726    1214          8β-methyl-9α/β,15-dihy-                                        droxy-17,17-dimethyl-                                                          13-trans-prostenoic                                                            acid                                                     1727    1215          8α-methyl-9α/β,15-dihy-                                       droxy-17,17-dimethyl-8-                                                        iso-13-trans-prosten-                                                          oic acid                                                 1728    1216          8β-methyl-9α/β,15-dihy-                                        droxy-17,17-dimethyl-13-                                                       cis-prostenoic acid                                      1729    1217          8α-methyl-9α/β,15-dihy-                                       droxy-17,17-dimethyl-8-                                                        iso-13-cis-prostenoic                                                          acid                                                     1730    1218          8β-methyl-9α/β,15-dihy-                                        droxy-13-trans,17-cis-                                                         prostadienoic acid                                       1731    1219          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-13-trans,17-                                                       cis-prostadienoic acid                                   1732    1220          8β-methyl-9α/β,15-dihy-                                        droxy-13-cis,17-cis-                                                           prostadienoic acid                                       1733    1221          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-13-cis,17-                                                         cis-prostadienoic acid                                   1734    1222          8β-methyl-9α/β,15-dihy-                                        droxy-20-ethyl-13-trans-                                                       prostenoic acid                                          1735    1223          8α-methyl-9α/β,15-dihy-                                       droxy-20-ethyl-8-iso-                                                          13-trans-prostenoic                                                            acid                                                     1736    1224          8β-methyl-9α/β,15-dihy-                                        droxy-20-ethyl-13-cis-                                                         prostenoic acid                                          1737    1225          8α-methyl-9α/β,15-dihy-                                       droxy-20-ethyl-8-iso-                                                          13-cis-prostenoic acid                                   1738    1230          8β-methyl-9α/β,15-dihy-                                        droxy-7a,7b-bishomo-13-                                                        trans-prostenoic acid                                    1739    1231          8α-methyl-9α/β,15-dihy-                                       droxy-7a,7b-bishomo-8-                                                         iso-13-trans-prosten-                                                          oic acid                                                 1740    1232          8β-methyl-9α/β,15-dihy-                                        droxy-7a,7b-bishomo-13-                                                        cis-prostenoic acid                                      1741    1233          8α-methyl-9α/β,15-dihy-                                       droxy-7a,7b-bishomo-8-                                                         iso-13-cis-prostenoic                                                          acid                                                     1742    1234          8β-methyl-9α/β,15-dihy-                                        droxy-2,20-bisethyl-13-                                                        trans-prostenoic acid                                    1743    1235          8α-methyl-9α/β,15-dihy-                                       droxy-2,20-bisethyl-8-                                                         iso-13-trans-prosten-                                                          oic acid                                                 1744    1236          8β-methyl-9α/β,15-dihy-                                        droxy-2,20-bisethyl-13-                                                        cis-prostenoic acid                                      1745    1237          8α-methyl-9α/β,15-dihy-                                       droxy-2,20-bisethyl-8-                                                         iso-13-cis-prostenoic                                                          acid                                                     1746    1238          8β-methyl-9α/β,15-dihy-                                        droxy-3-oxa-16,16-di-                                                          methyl-13-trans-pros-                                                          tenoic acid                                              1747    1239          8α-methyl-9α/β,15-dihy-                                       droxy-3-oxa-16,16-di-                                                          methyl-8-iso-13-trans-                                                         prostenoic acid                                          1748    1240          8β-methyl-9α/β,15-dihy-                                        droxy-3-oxa-16,16-di-                                                          methyl-13-cis-prosten-                                                         oic acid                                                 1749    1241          8α-methyl-9α/β,15-dihy-                                       droxy-3-oxa-16,16-di-                                                          methyl-8-iso-13-cis-                                                           prostenoic acid                                          1750    1242          8β-methyl-9α/β,15-dihy-                                        droxy-3-oxa-13-trans,17-                                                       cis-prostadienoic acid                                   1751    1243          8α-methyl-9α/β,15-dihy-                                       droxy-3-oxa-8-iso-13-                                                          trans,17-cis-prostadi-                                                         enoic acid                                               1752    1244          8β-methyl-9α/β,15-dihy-                                        droxy-3-oxa-13-cis,17-                                                         cis-prostadienoic acid                                   1753    1245          8α-methyl-9α/β,15-dihy-                                       droxy-3-oxa-8-iso-13-                                                          cis,17-cis-prostadien-                                                         oic acid                                                 1754    1246          8β-methyl-9α/β,15-dihy-                                        droxy-7-nor-20-methyl-                                                         13-trans-prostenoic                                                            acid                                                     1755    1247          8α-methyl-9α/β,15-dihy-                                       droxy-7-nor-20-methyl-                                                         8-iso-13-trans-pros-                                                           tenoic acid                                              1756    1248          8β-methyl-9α/β,15-dihy-                                        droxy-7-nor-20-methyl-                                                         13-cis-prostenoic acid                                   1757    1249          8α-methyl-9α/β,15-dihy-                                       droxy-7-nor-20-methyl-                                                         8-iso-13-cis-prosteno-                                                         ic acid                                                  1758    1250          8β-methyl-9α/β,15-dihy-                                        droxy-2-fluoro-17,17-                                                          dimethyl-13-trans-                                                             prostenoic acid                                          1759    1251          8α-methyl-9α/β,15-dihy-                                       droxy-2-fluoro-17,17-                                                          dimethyl-8-iso-13-                                                             trans-prostenoic acid                                    1760    1252          8β-methyl-9α/β,15-dihy-                                        droxy-2-fluoro-17,17-                                                          dimethyl-13-cis-pros-                                                          tenoic acid                                              1761    1253          8α -methyl-9α/β,15-dihy-                                      droxy-2-fluoro-17,17-                                                          dimethyl-8-iso-13-cis-                                                         prostenoic acid                                          1762    1254          8β-methyl-9α/β,15-dihy-                                        droxy-10a-homo-13-trans-                                                       prostenoic acid                                          1763    1255          8α-methyl-9α/β,15-dihy-                                       droxy-10a-homo-8-iso-                                                          13-trans-prostenoic                                                            acid                                                     1764    1256          8β-methyl-9α/β,15-dihy-                                        droxy-10a-homo-13-cis-                                                         prostenoic acid                                          1765    1257          8α-methyl-9α/β,15-dihy-                                       droxy-10a-homo-8-iso-                                                          13-cis-prostenoic acid                                   1766    1258          8β-methyl-9α/β,15-dihy-                                        droxy-2-phenyl-20-meth-                                                        yl-13-trans-prostenoic                                                         acid                                                     1767    1259          8α-methyl-9α/β,15-dihy-                                       droxy-2-phenyl-20-meth-                                                        yl-8-iso-13-trans-pros-                                                        tenoic acid                                              1768    1260          8β-methyl-9α/β,15-dihy-                                        droxy-2-phenyl-20-meth-                                                        yl-13-cis-prostenoic                                                           acid                                                     1769    1261          8α-methyl-9α/β,15-dihy-                                       droxy-2-phenyl-20-meth-                                                        yl-8-iso-13-cis-prosten-                                                       oic acid                                                 1770    1262          8β-methyl-9α/β,15-dihy-                                        droxy-5-cis,13-trans,17-                                                       cis-prostatrienoic acid                                  1771    1263          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-5-cis,13-                                                          trans,17-cis-prostatri-                                                        enoic acid                                               1772    1264          8β-methyl-9α/β,15-dihy-                                        droxy-5-cis,13-cis,17-                                                         cis-prostatrienoic acid                                  1773    1265          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-5-cis,13-                                                          cis,17-cis-prostatri-                                                          enoic acid                                               1774    1266          8β-methyl-9α/β,15-dihy-                                        droxy-5-cis,13-trans-                                                          prostadienoic acid                                       1775    1267          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-5-cis,13-                                                          trans-prostadienoic                                                            acid                                                     1776    1268          8β-methyl-9α/β,15-dihy-                                        droxy-5-cis,13-cis-                                                            prostadienoic acid                                       1777    1269          8α-methyl-9α/β,15-dihy-                                       droxy-8-iso-5-cis,13-                                                          cis-prostadienoic acid                                   1778    1270          8β-methyl-9α/β,15-dihy-                                        droxy-20-ethyl-5-cis,13-                                                       trans-prostadienoic                                                            acid                                                     1779    1271          8α-methyl-9α/β,15-dihy-                                       droxy-20-ethyl-8-iso-                                                          5-cis,13-trans-pros-                                                           tadienoic acid                                           1780    1272          8β-methyl-9α/β,15-dihy-                                        droxy-20-ethyl-5-cis-                                                          13-cis-prostadienoic                                                           acid                                                     1781    1273          8α-methyl-9α/β,15-dihy-                                       droxy-20-ethyl-8-iso-                                                          5-cis,13-cis-prosta-                                                           dienoic acid                                             ______________________________________                                    

EXAMPLES 1782-1815

Catalytic hydrogenation of the 13-trans-prostenoic acids or esters listed below in Table 44 by the procedure described in Example 699 furnishes the product prostanoic acids of the table.

                  TABLE 44                                                         ______________________________________                                                 Starting 13-   Products                                                        trans-prostenoic                                                                              8-methylprostanoic                                      Ex-     acid or ester of                                                                              acids or                                                ample   Example        esters                                                  ______________________________________                                         1782    1206           Methyl 8β-methyl-9α/β,                                         15-dihydroxy-                                                                  prostanoate                                             1783    1207           Methyl 8α-methyl-9α/β,                                        15-dihydroxy-8-iso-                                                            prostanoate                                             1784    1210           Ethyl 8β-methyl-9α/β,                                          15-dihydroxy-16,16-                                                            dimethyl-prostanoate                                    1785    1226           Decyl 8β-methyl-9α/β.                                          15-dihydroxy-20-methyl-                                                        prostanoate                                             1786    1655           8β-methyl-9-oxo-15-di-                                                    hydroxy-prostanoic acid                                 1787    1656           8α-methyl-9-oxo-15-di-                                                   hydroxy-8-iso-prostan-                                                         oic acid                                                                       oic acid                                                1788    1659           8β-methyl-9α/β,15-di-                                          hydroxy-prostanoic acid                                 1789    1660           8α-methyl-9α/β,15-di-                                         hydroxy-8-iso-prostan-                                                         oic acid                                                1790    1678           8β-methyl-9-oxo-15-hy-                                                    droxy-7a,7b-bishomo-                                                           prostanoic acid                                         1791    1683           8α-methyl-9-oxo-15-                                                      hydroxy-2,20-bisethyl-                                                         8-iso-prostanoic acid                                   1792    1686           8β-methyl-9-oxo-15- -  hydroxy-3-oxa-16,16-                               dimethyl-prostanoic                                                            acid                                                    1793    1694           8β-methyl-9-oxo-15-                                                       hydroxy-7-nor-20-                                                              methyl-prostanoic acid                                  1794    1702           8β-methyl-9-oxo-15-                                                       hydroxy-10a-homo-                                                              prostanoic acid                                         1795    1523           8β-methyl-9α/β.11α,15-                                   trihydroxy-prostanoic                                                          acid                                                    1796    1524           8α-methyl-9α/β,11α,15-                                  trihydroxy-8-iso-                                                              prostanoic acid                                         1797    1527           8β-methyl-9α/β,11α,15-                                   trihydroxy-16,16-di-                                                           methyl-prostanoic acid                                  1798    1531           8β-methyl-9α/β,11α,15-                                   trihydroxy-17,17-di-                                                           methyl-prostanoic acid                                  1799    1539           8β-methyl-9α/β-11α,15-                                   trihydroxy-20-ethyl-                                                           prostanoic acid                                         1800    1552           8α-methyl-9α/β,11α,15-                                  trihydroxy-7a,7b-bis-                                                          homo-8-iso-prostanoic                                                          acid                                                    1801    1551           8β-methyl-9α/β,11α,15-                                   trihydroxy-7a,7b-bis-                                                          homo-prostanoic acid                                    1802    1555           8β-methyl-9α/β,11α,15-                                   trihydroxy-2-ethyl-                                                            prostanoic acid                                         1803    1559           8β-methyl-9α/β,11α,15-                                   trihydroxy-3,3,20-tri-                                                         methyl-prostanoic acid                                  1804    1563           8β-methyl-9α/β,11α,15-                                   trihydroxy-3-oxa-                                                              prostanoic acid                                         1805    1567           8β-methyl-9α/β,11α,15-                                   trihydroxy-3-oxa-16,                                                           16-dimethyl-prostanoic                                                         acid                                                    1806    1587           8β-methyl-9α/β,11α,15-                                   trihydroxy-7a-homo-                                                            16,16-dimethyl-pro-                                                            stanoic acid                                            1807    1643           Ethyl 8β-methyl-9α/β,                                          11α,15-trihydroxy-3-                                                     oxa-17,17-dimethyl-                                                            prostanoic acid                                         1808    1816           8β,15-dimethyl-9α/β,15-                                        dihydroxy-prostanoic                                                           acid                                                    1809    1817           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-prostanoic                                                          acid                                                    1810    1819           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-8-iso-                                                              prostanoic acid                                         1811    1834           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-                                                       prostanoic acid                                         1812    1835           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-                                                        prostanoic acid                                         1813    1837           8α,15-dimethyl-9-oxo-                                                    11α,15-dihydroxy-8-                                                      iso-prostanoic acid                                     1814    1843           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-7a,                                                     7b-bishomo-prostanoic                                                          acid                                                    1815    1849           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-3-                                                      oxa-prostanoic acid                                     ______________________________________                                    

EXAMPLES 1816-1859

Treatment by the procedure described in Example 1082 of the 8-methyl-9α/β,15-dihydroxy-prostenoic acids listed in Table 45 below successively with 2,3-dichloro-5,6-dicyanobenzoquinone to give the corresponding 15-keto derivatives; 2.4 equivalents each of triethylamine and trimethylsilyl chloride to give the corresponding 9α/β-O-trimethylsilyl ether trimethylsilyl prostenoate ester in the instance of the 11α-hydroxy derivatives an additional 1.1 equivalent each of triethylamine and trimethylsilyl chloride is used and the 11α-O-trimethylsilyl ether derivative is obtained); methyl magnesium bromide to give the 15-methyl-15-hydroxy bis or tris trimethylsilyl blocked ether-ester; methanol-water-acetic acid for deblocking of the trimethylsilyl ether and ester blocking groups to give the listed 9α/β-hydroxy-15-methyl-15-hydroxy derivatives. In the 11-deoxy series treatment of these 9α/β-hydroxy-15-methyl-15-hydroxy products with Collins reagent in methylene chloride provides the corresponding 11-deoxy-9-oxo-15-hydroxy-15-methyl-prostenoic acids, also listed in the table. In the 11α-hydroxy series, treatment of the 9α/β, 11α-15-trihydroxy-15-methyl derivatives with 1.1 molar equivalents each of triethylamine and trimethylsilyl chloride provides, the corresponding 11α-O-trimethylsilyloxy-9α/β,15-dihydroxy derivative, which on oxidation in the usual way with Collins reagent in methylene chloride followed by silyl ether cleavage (treatment with methanol-water-acetic acid by the procedure described in Example 1082) provides the corresponding 9-oxo-11α,15-dihydroxy-15-methyl-prostenoic acids of the Table.

                  TABLE 45                                                         ______________________________________                                                 Starting 9α/β,(or                                                   9α),15-dihydroxy-                                                        or 9α/β (or 9α),                                                             Product                                                         11α,15-trihydroxy                                                                       8,15-dimethyl-15-hy-                                    Ex-     derivative of  droxy-prostanoic                                        ample   Example        acids                                                   ______________________________________                                         1816    1659           8β,15-dimethyl-9α,β,15-                                        dihydroxy-13-trans-                                                            prostenoic acid                                         1817    1659           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-13-trans-                                                           prostenoic acid                                         1818    1660           8α,15-dimethyl-9α,15-                                              dihydroxy-8-iso-13-                                                            trans-prostenoic acid                                   1819    1660           8α,15-dimethyl-9-oxo-                                                    15-hydroxy-8-iso-13-                                                           trans-prostenoic acid                                   1820    1730           8β,15-dimethyl-9α/β,15-                                        dihydroxy-13-trans,17-                                                         cis-prostadienoic acid                                  1821    1730           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-13-trans-                                                           17-cis-prostadienoic                                                           acid                                                    1822    1731           8α,15-dimethyl-9α/β,15-                                       dihydroxy-8-iso-13-                                                            trans,17-cis-prosta-                                                           dienoic acid                                            1823    1731           8α,15-dimethyl-9-oxo-                                                    15-hydroxy-8-iso-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                            1824    1738           8β,15-dimethyl-9α/β,                                           15-dihydroxy-7a,7b-                                                            bishomo-13-trans-                                                              prostenoic acid                                         1825    1738           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-7a,7b-bis-                                                          homo-13-trans-prost-                                                           enoic acid                                              1826    1746           8β,15-dimethyl-9α/β,                                           15-dihydroxy-3-oxa-16,                                                         16-dimethyl-13-trans-                                                          prostenoic acid                                         1827    1746           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-3-oxa-16,                                                           16-dimethyl-13-trans-                                                          prostenoic acid                                         1828    1750           8β,15-dimethyl-9α/β,                                           15-dihydroxy-3-oxa-                                                            13-trans,17-cis-                                                               prostadienoic acid                                      1829    1750           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-3-oxa-13-                                                           trans,17-cis-prosta-                                                           dienoic acid                                            1830    1770           8β,15-dimethyl-9α/β,                                           15-dihydroxy-5-cis,                                                            13-trans,17-cis-prosta-                                                        trienoic acid                                           1831    1770           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-5-cis,13-                                                           trans,17-cis-prosta-                                                           trienoic acid                                           1832    1778           8β,15-dimethyl-9α/β,                                           15-dihydroxy-20-ethyl-                                                         5-cis,13-trans-                                                                prostadienoic acid                                      1833    1778           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-20-ethyl-5-                                                         cis,13-trans-prosta-                                                           dienoic acid                                            1834    1523           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-13-                                                    trans-prostenoic acid                                   1835    1523           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-13-                                                     trans-prostenoic acid                                   1836    1524           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-8-                                                     iso-13-trans-pros-                                                             tenoic acid                                             1837    1524           8α,15-dimethyl-9-oxo-                                                    11α,15-dihydroxy-                                                        8-iso-13-trans-                                                                prostenoic acid                                         1838    1535           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-13-                                                    trans,17-cis-prosta-                                                           dienoic acid                                            1839    1535           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-13-                                                     trans,17-cis-prosta-                                                           dienoic acid                                            1840    1539           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-20-                                                    ethyl-13-trans-pro-                                                            stenoic acid                                            1841    1539           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-20-                                                     ethyl-13-trans-pro-                                                            stenoic acid                                            1842    1551           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-7a,                                                    7b-bishomo-13-trans-                                                           prostenoic acid                                         1843    1551           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-7a,                                                     7b-bishomo-13-trans-                                                           prostenoic acid                                         1844    1555           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-2-                                                     ethyl-13-trans-                                                                prostenoic acid                                         1845    1555           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-2-                                                      ethyl-13-trans-                                                                prostenoic acid                                         1846    1559           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-3,3,                                                   20-trimethyl-13-trans-                                                         prostenoic acid                                         1847    1559           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-3,3                                                     20-trimethyl-13-trans-                                                         prostenoic acid                                         1848    1563           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-3-                                                     oxa-13-trans-prostenoic                                                        acid                                                    1849    1563           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-3-                                                      oxa-13-trans-prostenoic                                                        acid                                                    1850    1571           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-3-                                                     oxa-13-trans,17-cis-                                                           prostadienoic acid                                      1851    1571           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-3-oxa-                                                  13-trans,17-cis-prosta-                                                        dienoic acid                                            1852    1599           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-5-                                                     cis,13-trans-prosta-                                                           dienoic acid                                            1853    1599           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-5-                                                      cis,13-trans-prosta-                                                           dienoic acid                                            1854    1603           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-5-cis,                                                 13-trans,17-cis-prosta-                                                        trienoic acid                                           1855    1603           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-5-                                                      cis,13-trans,17-cis-                                                           prostatrienoic acid                                     1856    1611           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-4-nor-                                                 20-methyl-5-cis,13-                                                            trans-prostadienoic                                                            acid                                                    1857    1611           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-4-                                                      nor-20-methyl-5-cis,                                                           13-trans-prostadienoic                                                         acid                                                    1858    1623           8β,15-dimethyl-9α/β,                                           11α,15-trihydroxy-4a,                                                    4b-bishomo-5-cis,13-                                                           trans,17-cis-prosta-                                                           trienoic acid                                           1859    1623           8β,15-dimethyl-9-oxo-                                                     11α,15-dihydroxy-4a,                                                     4b-bishomo-5-cis,13-                                                           trans,17-cis-prosta-                                                           trienoic acid                                           ______________________________________                                    

EXAMPLES 1860-1876

Treatment of the 8,15-dimethyl-9-oxo-11α-hydroxy derivatives listed in Table 46 below with aqueous acetic acid by the procedure described in Example 1387 is productive of the corresponding 10-prostenoic acid products of the table.

                  TABLE 46                                                         ______________________________________                                                 Starting 8,15-di-                                                              methyl-9-oxo-11α-                                                                       Product                                                 Ex-     hydroxy deriva-                                                                               8,15-dimethyl-9-oxo-                                    ample   tives of Example                                                                              10-prostenoic acid                                      ______________________________________                                         1860    1835           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-10,13-trans-                                                        prostadienoic acid                                      1861    1837           8α,15-dimethyl-9-oxo-                                                    15-hydroxy-8-iso-10,                                                           13-trans-prostadienoic                                                         acid                                                    1862    1839           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-10,13-trans,                                                        17-cis-prostatrienoic                                                          acid                                                    1863    1841           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-20-ethyl-                                                           10,13-trans-prosta-                                                            dienoic acid                                            1864    1843           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-7a,7b-bis-                                                          homo-10,13-trans-                                                              prostadienoic acid                                      1865    1845           8β,15-dimethyl-9-oxo-15-                                                  hydroxy-2-ethyl-10,13-                                                         trans-prostadienoic                                                            acid                                                    1866    1847           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-3,3,20-tri-                                                         methyl-10,13-trans-                                                            prostadienoic acid                                      1867    1849           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-3-oxa-10,13-                                                        trans-prostadienoic                                                            acid                                                    1868    1851           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-3-oxa-10,                                                           13-trans,17-cis-prosta-                                                        trienoic acid                                           1869    1853           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-5-cis,10,13-                                                        trans-prostatrienoic                                                           acid                                                    1870    1855           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-5-cis,10,                                                           13-trans,17-cis-prosta-                                                        tetraenoic acid                                         1871    1857           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-4-nor-20-                                                           methyl-5-cis,10,13-                                                            trans-prostatrienoic                                                           acid                                                    1872    1859           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-4a,4b-bis-                                                          homo-5-cis,10,13-trans,                                                        17-cis-prostatetraenoic                                                        acid                                                    1873    1812           8β,15-dimethyl-9-oxo-15-                                                  hydroxy-10-prostenoic                                                          acid                                                    1874    1815           8β,15-dimethyl-9-oxo-15-                                                  hydroxy-3-oxa-10-                                                              prostenoic acid                                         1875    1814           8β,15-dimethyl-9-oxo-15-                                                  hydroxy-7a,7b-bishomo-                                                         10-prostenoic acid                                      1876    1813           8β,15-dimethyl-9-oxo-                                                     15-hydroxy-8-iso-10-                                                           prostenoic acid                                         ______________________________________                                    

EXAMPLE 1877 Preparation of 3-methoxy-1-octyne

To an ice-cooled solution of 63 g. of 1-octyn-3-ol in 300 ml. of dimethoxyethane is added under an inert atmosphere 312 ml. of 1.6 M n-butyllithium in hexane dropwise over 1 hour. To the mixture is then added 145 g. of methyl iodide and the resulting mixture is stirred at ambient temperatures for 24 hours and then heated to 60° C. for 1 hour. The mixture is cooled and poured into cold dilute hydrochloric acid. The organic phase is separated, washed with water and saturated brine, dried (Na₂ SO₄), and evaporated to an oil, dried (Na₂ SO₄), and evaporated to an oil. Fractional distillation of the oil in vacuo yields the product as a colorless oil.

EXAMPLE 1878 Preparation of 1-Iodo-3-methoxy-trans-1-octene

Treatment of 3-methoxy-1-octyne (Example 1877) with disiamylborane, trimethylamine oxide, sodium hydroxide and iodine by the procedure described in Example 996 furnishes the title product.

EXAMPLE 1879 Preparation of 3-Methoxy-trans-1-octenyl lithium

Treatment of 1-iodo-3-methoxy-trans-1-octene (Example 1878) with butyl lithium in the manner of Example 961 pro provides a toluene-hexane solution of the subject trans-vinyl lithium derivative.

EXAMPLE 1880 Preparation of Lithium (3-methoxy-trans-1-octenyl)trimethylalanate

The subject alanate in hydrocarbon solution is prepared according to the method of Example 963 from a hydrocarbon solution of 3-methoxy-trans-1-octenyl lithium (Example 1879 ) and trimethylaluminum.

EXAMPLES 1881-1895

Treatment of the cycloalkenones listed in Table 47 with lithium (3-methoxy-trans-1-octenyl)trimethylalanate (Example 1880) by the procedure described in Example 957 with the omission of the 80% aqueous acetic acid treatment (80° C., 1 hour) followed by saponfication of the intermediate alkyl prostenoates by the procedure described in Example 122 furnishes the product 9-oxo-15-methoxy-13-trans-prostenoic acids of the table.

                  TABLE 47                                                         ______________________________________                                                 Starting cyclo-                                                                               Product 9-oxo-15-                                       Ex-     alkenone of    methoxy-13-trans-                                       ample   Example        prostenoic acid                                         ______________________________________                                         1881    23             9-oxo-7a,7b-bishomo-                                                           15-methoxy-13-trans-                                                           prostenoic acid                                         1882    31             9-oxo-2-ethyl-15-                                                              methoxy-13-trans-pro-                                                          stenoic acid                                            1883    41             9-oxo-3,3-dimethyl-                                                            15-methoxy-13-trans-                                                           prostenoic acid                                         1884    46             9-oxo-3-oxa-15-methoxy-                                                        13-trans-prostenoic                                                            acid                                                    1885    53             9-oxo-7-nor-15-methoxy-                                                        13-trans-prostenoic                                                            acid                                                    1886    70             9-oxo-2-fluoro-15-                                                             methoxy-13-trans-                                                              prostenoic acid                                         1887    74             9-oxo-7a-homo-15-                                                              methoxy-13-trans-pro-                                                          stenoic acid                                            1888    79             9-oxo-2-phenyl-15-                                                             methoxy-13-trans-pro-                                                          stenoic acid                                            1889    99             9-oxo-2-methyl-15-                                                             methoxy-13-trans-pro-                                                          stenoic acid                                            1890    111            9-oxo-10a-homo-15-                                                             methoxy-13-trans-                                                              prostenoic acid                                         1891    118            9-oxo-3-thia-15-                                                               methoxy-13-trans-                                                              prostenoic acid                                         1892    900            9-oxo-15-methoxy-5-                                                            cis,13-trans-pro-                                                              stadienoic acid                                         1893    1144           9-oxo-4-nor-15-methoxy-                                                        13-trans-prostadienoic                                                         acid                                                    1894    1145           9-oxo-4-homo-15-                                                               methoxy-5-cis,13-                                                              trans-prostadienoic                                                            acid                                                    1895    1146           9-oxo-4a,4b-bishomo-                                                           15-methoxy-13-trans-                                                           prostadienoic acid                                      ______________________________________                                    

EXAMPLES 1896-1910

Treatment of the 9-oxo-15-methoxy-13-trans-prostenoic acids listed in Table 48 below with lithium perhydro-9b-boraphenalylhydride by the procedure described in Example 737 furnishes the 9α-hydroxy-15-methoxy-13-trans-prostenoic acids of the Table.

                  TABLE 48                                                         ______________________________________                                                 Starting 9-oxo-                                                                15-methoxy-13- Product 9α-hydroxy-15-                                    trans-prosten- methoxy-13-trans-                                       Ex-     oic acid of    prostenoic                                              ample   Example        acid                                                    ______________________________________                                         1896    1881           9α-hydroxy-7a,7b-bis-                                                    homo-15-methoxy-13-                                                            trans-prostenoic acid                                   1897    1882           9α-hydroxy-2-ethyl-                                                      15-methoxy-13-trans-                                                           prostenoic acid                                         1898    1883           9α-hydroxy-3,3-dimethyl-                                                 15-methoxy-13-trans-                                                           prostenoic acid                                         1899    1884           9α-hydroxy-3-oxa-15-                                                     methoxy-13-trans-                                                              prostenoic acid                                         1900    1885           9α-hydroxy-7-nor-15-                                                     methoxy-13-trans-pro                                                           prostenoic acid                                         1901    1886           9α-hydroxy-2-fluoro-                                                     15-methoxy-13-trans-                                                           prostenoic acid                                         1902    1887           9α-hydroxy-7a-homo-                                                      15-methoxy-13-trans-                                                           prostenoic acid                                         1903    1888           9α-hydroxy-2-phenyl-                                                     15-methoxy-13-trans-                                                           prostenoic acid                                         1904    1889           9α-hydroxy-2-methyl-                                                     methoxy-13-trans-                                                              prostenoic acid                                         1905    1890           9α-hydroxy-10a-homo-                                                     15-methoxy-13-trans-                                                           prostenoic acid                                         1906    1891           9α-hydroxy-3-thia-15-                                                    methoxy-13-trans-                                                              prostenoic acid                                         1907    1892           9α-hydroxy-15-methoxy-                                                   5-cis,13-trans-prosta-                                                         dienoic acid                                            1908    1893           9α-hydroxy-4-nor-15-                                                     methoxy-5-cis,13-                                                              trans-prostadienoic                                                            acid                                                    1909    1894           9α-hydroxy-4-homo-15-                                                    methoxy-5-cis,13-trans-                                                        prostadienoic acid                                      1910    1895β     9α-hydroxy-4a,4b-bis-                                                    homo-15-methoxy-13-                                                            trans-prostenoic acid                                   ______________________________________                                    

EXAMPLE 1911 Preparation of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol

A solution of 5.0 g (35 mmoles) of 5-hydroxy-2,3-oxidocyclopentylacetaldehyde-γ-lactol (isomeric mixture; E. J. Corey and R. Noyori, Tetrahedron Letters, 1970. 311) in 25 ml. of DMSO is added during 0.5 minutes at 20° C to a stirred solution of the Withig reagent [E. J. Corey et al., JACS, 91 5675 (1969) ; also Example 1108] and dimsyl sodium prepared from 23.5 g. (53 mmoles) of 4-carboxybutyltriphenylphosphonium bromide, 6.1 g. (140 mmoles) of 57% sodium hydride dispersion, and 230 ml. of DMSO (dimethylsulfoxide).

The solution is stirred at ambient temperatures for 2 hours and poured into a stirred mixture of methylene chloride, ice, and hydrochloric acid. The reaction mixture is worked up as described in Example 1105, and the crude product is purified by dry column chromatography on silica gel to provide the title compound (mixture of two stereoisomers) as an oil, IR (film) 3450, 1710, and 832 cm⁻¹.

EXAMPLE 1912 Preparation of 2-(6-carboxy-2cis-hexenyl)-3,4-oxidocyclopentanone

A stirred solution of 2.98 g. (13.2 mmoles) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanol (Example 1911) in 66 ml. of acetone is treated dropwise with 3.30 ml. of 8N chromic acid in 8N M₂ SO₄ during 20 minutes at -10° to -5° C. The solution is stirred at -5° C . for 10 minutes and treated successively with a few drops of iospropanol and 12 ml. of water. The mixture is filtered, and the filtrate is concentrated saturated with sodium chloride, and extracted with ethyl acetate. The extract is washed with brine, dried over MgSO₄, and evaporated to give an oil, IR (film) 1740, 1710, and 840 cm⁻¹.

EXAMPLE 1913 Preparation of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one

A solution of (pH or 10.2-10.5) of 2.42 g. (10.8 mmoles ) of 2-(6-carboxy-2-cis-hexenyl)-3,4-oxidocyclopentanone (Example 1912) 4.58 g. (43.2 mmoles) of sodium carbonate, and 216 ml. of water is allowed to stand at room temperatures under nitrogen for 24 hours. The solution is acidified at 15° C. with hydrochloric acid and extracted with ethyl acetate. The extract is washed with brine, dried over MgSO₄, and evaporated to give an oil; IR (film) 1700 (carbonyl groups) and 1630 cm⁻¹ (conjugated olefin); NMR 7.11 (1), 5.54 (2) and 4.95 (1)δ. 

We claim:
 1. A racemic mixture of the formula: ##STR38## wherein n is the integer 1 or 2, m is the integer 5 or 6, R₁ is hydrogen or alkyl having up to 3 carbon atoms, R₂ is 2-cis-pentenyl or 1,1-dimethyl-n-pentyl, and R₃ is hydrogen or methyl with the proviso that when R₂ is 1,1-dimethyl-n-pentyl then R₃ must be hydrogen; and the pharmaceutically acceptable cationic salts thereof when R₁ is hydrogen.
 2. The racemic mixture according to claim 1, dl-9-oxo-15-hydroxy-13-trans,17-cis-prostadienoic acid.
 3. The racemic mixture according to claim 1, dl-9-oxo-15-hydroxy-16,16-dimethyl-13-trans-prostenoic acid.
 4. The racemic mixture according to claim 1, dl-9-oxo-15-hydroxy-15-methyl-13-trans,-17-cis-prostadienoic acid.
 5. The racemic mixture according to claim 1, dl-9-oxo-15-hydroxy-10α-homo-16,16-dimethyl-13-trans-prostenoic acid.
 6. The racemic mixture according to claim 1, dl-9-oxo-7-nor-15-hydroxy-13-trans,17cis-prostadienoic acid.
 7. The racemic mixture according to claim 1, dl-9-oxo-7-nor-15-hydroxy-16,16-dimethyl-13-trans-prostenoic acid.
 8. The racemic mixture according to claim 1, dl-9-oxo-7-nor-15-hydroxy-15-methyl-13-trans,17cis-prostadienoic acid. 